PHARMACOUNETICS AND PHARMACOD YNAMICS OF CRUSHED AND INTACT NIFEDIPINE PROLONGED ACTION (ADALA T @ PA) TABLETS fiV

HEL THY WE VOL UNTEERS

A thesis submitted in the conformity with the requirements For the degree of Master of Science.

Graduate Department of the Faculty of Pharmacy. University of Toronto

O Copyright by Robert Marc Lepage 2000

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Robert Lepage M.Sc., Scott Walker M.Phm, Fran Paradiso-Hardy M.Phm., Martin Myers M.D., Sunnybrook & Wornen's College Health Science Center, University of Toronto, Toronto, Ontario. October 2000.

Abstract

The Pharmacokinetics and Pharmacodynamics of Intact and Crushed Nifedipine Prolonged Action (PA) Tablets

Short-acting nifedipine capsules are discouraged for the treatment of acute asymptornatic hypertension (HT) due to serious adverse events associated with precipitous BP reduction. While intact nifedipine PA tablets provide a more gradua1 and sustained BP reduction, the antihypertensive properties of crushed PA tablets for nasogastric (NG) administration are unknown. The pharmacokinetics [area under the curve (AUC), peak concentration (Cmax), time to peak concentration (Trnax), absorption rate (Ka), half-life] and p hamacodynamics (magnitude and duration of BP reduction) of single-dose intact and crushed nifedipine PA 20 mg tablets in 21 healthy, male volunteers were compared in a randomized, open-label, crossover study. Data are presented as mean I SD.

Intact Tablet Crushed Tablet P-Value AUCk (ng*min/ml) 207.2 f 87.6 254.2 f 108.5 0.0001

Cmax (ng/ml) 32k 14 40 2 14 0.0003 Tmax (min) 112f54 96 + 45 NS Ka (min-') 0.055 k 0.051 0.063 f 0.1 37 NS

A SBP (mmHg) -14.0 f 6.4 -1 1.3 + 6.0 NS A DBP (mmHg) -1 0.8 -t 5.9 -9.1 -t 5.4 NS

No significant differences were observed between the intact and crushed PA tablets with respect to the magnitude and duration of BP reduction, rate of absorption and elimination. Crushed PA tablets resulted in greater absorption as reflected in the higher AUC and Cmax.

Conclusion: The small difference in serum nifedipine concentration between the crushed and intact PA tablets did not result in clinical or statistical differences in BP reduction. Crushed nifedipine PA tablets provide a therapeutic alternative in the treatment of acute HT.

TECHNICAL ABSTRACT

PROLOIVGED ACTION (ADALA T @PA) TA BLETS IN HGIL THY, MALE VOLUNTEERS Robert Leoape B.Sc.H., Scott Walker M.Sc. Phm., Fran Paradiso-Hardy Pharm. D., Martin Myers M.D., Sunnybrook & Women's College Health Science Centre, University of Toronto, Ontario, Canada

CONTEXT: Nifedipine is a calcium channel influx inhibitor used in the treatment of chronic stable angina and hypertension. Sublingual (SL) nifedipine was used widespread for the treatrnent ofacute hypertensive emergencies. However. its use nas been criticized due to seveni reported cases of abrupt and precipitous talls in

BP. The apparent acute hypotensive response results fiom rapid absorption in the GI tract and not the buccal cavity. Unpublished information suggests that the sustained-release properties of the microcrystalline formulation of nifedipine prolonged-action tablet (AdalatB PA) are retained following cnishing. Objective: To compare the pharmacokinetic properties (rate and extent of absorption) and the pharmacodynarnic propenies (magnitude and duration of BP reduction) of intact and crushed prolonged-action (PA) nifedipine tablets (Adalat PA@) in healthy male volunteers. DESIGN: This is an open-label. randomized. crossover study. Subjects were instructed to: (i) abstain from catTeine. grapefruit juice, and alcoholic beverages for 48 hours prior to each treatment period md throughout the study day: (ii) fast. starting 2200h the evening prior to the study day and remained fasting t'or four (4) hours afler the first dose of the study day with access to water only. Blood sarnples were taken fiom an indwelling antecubital venous catheterat tirnes 0. 0.25.0.5. 0.75. 1. 1.33. 1.67.2.2.5. 3.4.6. 8. 10 & 12 hours after drug administration. S ~ ~ ~ i i r i c : Large teaching hospital in Ontario Canada. P:\R'TICIPANTS: A total of 21 healthy male non-smoking volunteers. with no major health problems and not on any rnedications participated in the study. I~TERVE;YTIONS: Subjects were randomly assigned to receive either crushed or intact nifedipine (20 mg) followed by the altemare on the next study day. M m OL~TLOME MEASURES: In Canada the 90% contldence interval for relative ratio of AUC must fall completely within the 80-125% boundary to dernonstrate equivaience of extent of absorption. The relative ratio of Cmav must faIl within 80- 1 XO/O to demonstrate equivalence of rate of absorption. The concentration of nifedipine will be assayed by GC-EC. Peak serum concentration (C,) and time to peak semm concentration (Tm,) will be detemined from individual serurn concentration-time profiles. Area under the serum concentration-time profiles over the dosing interval (From zero to 12 hours: AUC6li) will be calculated using the log-linear tmpezoidal rule. For kinetic vm'ables (C,. Auch, AUCG12). log transformation will be completed prior to analysis of variance (ANOVA). which utilizes the factors of sequence. period. formulation, and subject in the model.

alternative in the treatrnent of acute HT.

RESL'LTS:

AUC (ng*min/ml) Cmax (ng/rnl) Tmax (min) Ka (mi"*') Half-Iife (min) A SBP (mmHg) A DBP (mmHg)

Conclusions: The small dit'ference in serum nifedipine concentration between the crushed and intact PA tahlets did not result in clinical or statistical differences in BP reduction. Crushed nifedipine PA tablets provide a thenpeutic

Intact Tablet 207.2 2 87.6 3 1.7 ic 14.4 1 1 1.7t53.9

0.0637 1 O. 1374 128.7

- 13.0 + 6-4 -1 0.8 * 5.9

Crushed Tablet 254.2 +, 108.4 40.4 + t 3.9 95.8 .+ 45.1

0.055 1 k 0.0508 1 15.5

-1 1.3 k 6.0 -9.1 F 5.4

. pvalue 0.000 1 0.0003 NS NS NS NS NS

The author wishes to express his gratitude to the following penons:

Mr. Scott Walker. who's expertise makes him a superior educator. His high standard of excellence encouraged me to exceed my own expectations. Thank you for your continuing ouidance and the many doors you have opened for me in life. in the indiistry. academia and on &e ice.

Ms. F m Paradiso-Hardy. for helping me believe that 1 can attain the success 1 desire. and to never give up.

Dr. Martin Myers. For creating this study and providing a challenging academic environment.

Dr. Reina Bendayan. who always had invaluable input when 1 stnyed off course.

Ms. Alyssa "Ducky" Hodder. her editing skills. support. and love are unmatched. even though she doesn't understand why we do the things we do.

Mrs. Shirley Law. For her patience and Fnendship. Her guidance has been invaluable in the lab and on the cornputer.

Mr. Danny Lau. who always attempted to fix al1 the cornputer problems that 1 created with a smile. His understanding and friendship are much appreciated.

Dr. Sandn Tailor. for always smiling and sharing.

Lynda Adam and Katherine Balisle. Their generosity helped this study progress as smoothly as it did. even on weekends.

Dr. Tom Paton and the rest of the Senior staff of the Pharmacy Department at Sunnybrook and Women's Collage Health Science Center for their support. friendship. laughter. and encouragement.

TABLE OF CONTENTS CLINICAL ABSTRACT II

TECHhICAL ABSTRACT III

ACKNOWLEDGEMENTS IV

TABLE OF CONTENTS V

LIST OF ABBREVIATIONS VI11

LIST OF TABLES 1x1

LIST OF FIGURES XI

LIST OF APPENDICES XII

1.0 INTENT OF STUDY 1

2.0 OBJlElCTIVE 3

3.0 RESEARCH HYPOTHESIS 3

4.0 BACKGROUND 4

4.1 HYPERTENSION 4 4 . . 1 Definit iodClrrssificut ion 4 4.2 -2 Etioiogv/Pathugenesis 5 4.1.3 Trecltment 6 4.24 BIood Pressrrre ~bieasttremrnt 6

- -L 2.1 Definition/~ndicufiun/rl vai fub il@ 4 . 2 Mechmism ofn crian 8 4.2.3 Pharrnuco~vnamics 8 4 . 2 4 Pharmacokinetics 9

4.2.4.1 Absorption/Bioavailabili~ 9 4.2.4.2 Distribution 10 4.2.4.3 Metabolisrn and Elirnination 10 4.2.4.4 Haif Life (t%) 11

42.5 Therapeut ic Dose 14 4.26 Side Effectsi Drug Related Adverse Effects 14 4 2.7 Sublingual ivgedipine & The Literatrire I S

4.3 CRUSHED DRUGS IN THE LITERATURE 17 4.5 BIOEQU~VALENCE 19

4 . Conditcf of a BioeqzA&mx Study 22 4.6 POTENTIAL THEEWPEUTIC IMPLICATIONS 24

5.0 METHODS 25

5.1. i Basic Siiidy Design 25 5.1.2 Stu& Population dS 3 Incirision Criteria 25 5.1.4 E~clrisionCriteria 26

5.2 RESEARCH PROCEDURE 27 5 - 2 1 Base iine Stiidy Procedure 27

5.21. 1 Patient Physical 27 5.2.1 .Z Laboratory Tests 27

5-22 Study Duy Procedure - , '17

5.3 PRIMARY OUTCOMES 3 1 1 Phurmaco kinet ic 31 j. 3.2 Pharmcico kine tic .Anui'vsis 31 3 Fhurmuco~vnamics 33 5.3.4 Pharmaco~vnurnir .4 nrdysis 33

5.3 -4.1 Blood Pressure/Heart Rate Measurernents 33 5 -3 4.2 Mean Artenal Pres su re 33

5.4 SAMPLE SIZE 34 5.5 I Stut i.stictil.4 nulysis 35

INTER- & INTRA-SUBJECT VARIABILITY 36 B [OEQUIVALENCE TESTING 36

RESULTS 37

ETHICS APPROVAL 37 STUDY POPLrLATION 37 DEMOGRAPHICS 37 PH AR~L~ACOKINETIC RESULTS 39

6.4.1 A UCOO ,i 42 6. -1. L A C/COOr 44 6.4.3 Cmair 47 6.4.4 ka 50 6.4.5 CrndAUC j2 6.4.6 Tiag 54 6.4.7 ke 56 6-4.8 Tmcrc 58

6.5 OUTL~ERS 60 6 . . 1 Effects ofSirbjects 1 9 's Data on A UCKe!/Ka 61 6.1 2 Statistical A nalysis 63 6.5.3 Evalriation of Po tent i d Sources of Error 63

6.5.3. L Analysis Error 63 6.5.3.2 Dose 64 6.5.3.3 Labeling 65 6.5.3.4 Violating the Protocol 65

6.6 PHARMACODYNAMIC RESULTS 66 6.6.1 Blood Pressure Reduction 67

6.6.1.1 Systolic Blood Pressure 67 6.6.1.3 Diastolic Blood Pressure 69

6-62 Heurt Raie 71 6.6.3 ltltl P 73

6.7 INTER- & INTRA-SUBJECT VARIABILITY 75 6. ?. I Post Hoc Analysis - - ' 3

6.8 BIOEQUIVALENCE 76

7.0 DlSCUSSION 77

7.1 PHARMACOKINET~CS 77 " ! I Ertenr -,y '. 2.2 Rute -9 -1.3 TlagdTmar 8 I T1.4 ke 82

7.2 P H A R M A C O D ~ A M I C S 83 BIood Presszrre 83 Systolic BP T = O 83 Systotic BP Reduction 83 Diastoiic BP T = O 85 Diastolic BP 85

Heurt Raie 88 :tu P 90

8.0 CONCLUSIONS/RECOMMENDATlQNS 92

9.0 REFERENCES Y4

AIC ANOVA AUC BP BPM CBC Cmau cv CYP DBP ECG FDA G tTS HEENT HPB HR [SHIES IR I.V. N C ka ke LSD MAP ml mg MI mmHg MRC MRF NaOH NHANES NHCSC NG P-450 PA SC SD. SD SBP Tmax Tlag US Vd, XL.

Akaike Idonnation Criteria Analysis Of Variance Area Under the s e m concentration-tirne Curve Blood Pressure Beats Per Minute Complete Blood Count Peak S e m Concentration Coefficient of Variation Cytochrome DiastoIic Blood Pressure Electrocardiogram Fçderal Drue Administration GastoIntestinal Therapeutic (Transit) System Head. Eyes. Ears. Nose. Throat Health Protection Branch Heart Rate International Study of Hypertension In Blacks Immediate Release Intravenous Joint National Committee Absorption rate constant Elimination rate constant Least Signiticant Di fference Mean Arterial Pressure Milliliters Milligams Myocardial Infmcrction Millimeters of Mercury Medical Research Counci 1 Modified Retease Formulation Sodium Hydroxide National Heaith and Nutrition Examination Survey National Hypertension Control Strategy Committee Nasogastric P-450 metabolic system Prolonged Action Schwartz Cntena Standard Deviation Systolic Blood Pressure Tirne to peak Serurn concentration Lag tirne United States Volume of distribution at steady state Extended Release

LIST OF TABLES TABLE 1- CLASSIFICATION OF BLOOD PRESSURE FOR ADULTS AGED 18 YEARS AND OLDER ........ 3 TABLE 2- PHARMACOKINETIC PARAMETERS AUC . CMAX. TMAX . T% AND F FOR NIFEDIPINE

FOUND M THE LITERATURE ............................... ,,., .............................................................. 13 TABLE 3 - SAMPLE SIZE CALCULATIONS BASED ON [NTRA-SUBIECT VAR~ABILITY A N D MEAN

DIFFERENCE ........................................................................................................................ 34 TABLE 4 - INDIVIDUAL SUBJECT HEIGHT . WEIGHT, AGE. SBP. DBP . MAP AND HR AT THE TIME

OF PHYSICAL ASSESSMENT ................................................................................................... 38 TABLE 5 - SUMMARY OF THE MEAN PHARMACODYNAMIC DATA SBP. DBP . MAP AND HR FOR

2 1 SUBJECTS BASED ON INITIAL PHYSICAL ......................................................................... 38 TABLE 6 - COMPARISON OF THE PHARMACOKINETIC PARAMETERS OF CRUSHED AND INTACT

ADALAT @ PA TABLETS .................................................................................................... 39 TABLE 7 - AUCo-i2 (NG*H/~~L) ANALYSIS DATA ......................................................................... 43 TABLE 8 - FOUR WAY ANOVA COMPAR~NG CRUSHED AND LI TACT ADALAT @ PA FOR AREA

UNDER THE CONCENTRATION-TIME CURVE TO TIME 12 HOURS (AuCo.,?) .......... .. ........ 43 TABLE 9 - AUCoJ: (NG*H/ML) ANALYSIS DATA ........................... .. ...................................... 45 TABLE 1 O - FOUR WAY ANOVA COMPAR~NG CRUSHED A N D INTACT ADALAT @ PA FOR AREA

UNDER THE CONCENTRATION-TIME CURVE TO [NFINITY (AuCo, ) ..................................... 45 TABLE I 1 - CMAX (NG/ML) ANALYSE DATA .............................................................................. 48 TABLE 13 - FOUR WAY ANOVA CO~IPARING CRUSHED AND INTACT ADALAT @ PA FOR

MAXIRIUM PLASMA NIFEDIPME CONCENTRATIONS (CMAX) .......................................... 48 1 TABLE 1 3 - KA (MIN- ) ANALYSE DATA ...................................................................................... 31

TABLE 14 - FOUR WAY ANOVA COMPARING KACRCSCiED A N D ......................................... 51 t TABLE 15 . CMAX/AUC (H' ) ANALYSIS DATA .......................................................................... 53

TABLE 1 6 - FOUR WAY ANOVA COMPARING C M A X / A U C ~ ~ ~ ~ ~ ~ ~ ~ AND CMA.VAUC,~~ . ,~ ........... 53 TABLE 17 - TLAG (MM) ANALYSIS DATA .................................................................................... 55 TABLE 18 - FOUR WAY ANOVA COMPARING T L A G ~ ~ ~ ~ ~ ~ ~ AND T L A G ~ ~ ~ ~ FOR ADALAT @ PA . 55

t TABLE 19 - KE (MM' ) ANALYSIS DATA ....................................................................................... 57 TABLE 20 - FOUR WAY ANOVA COMPARING CRUSHED AND INTACT ADALAT @ PA FOR RATE OF

ELIMMATION (KE) ................................................................................................................ 57 TABLE 2 1 - TMAX (MIN) ANALYSIS DATA ................................................................................... 59 TABLE 22 - FOUR WAY ANOVA COMPARING T M A ~ ~ ~ ~ ~ ~ AND T M A X ~ ~ ~ ~ ~ ~ .............................. 39 TABLE 25 - COMPARISON OF PHARMACOKINETIC PARAMETERS W~TH AND WKHOUT POSSIBLE

OUTLIERS ............................................................................................................................. 62 TABLE 24 - PHARMACOKINETIC DATA FOR SUBJECT 19 ........................................... ., 62 TABLE 23 - RESULTS OF OUTLIER TESTS FOR SUBJECT 19 .......................................................... 63 TABLE 26 - MEAN PHARMACODYNAMIC PARAMETERS SBP . DBP, H R. MM ........................... 66 TABLE 27 - MEAN ~ X I ~ ~ U M . MINIMUM AND DIFFERENCE IN SBP AND DBP DATA ................. 66 TABLE 28 - FIVE WAY ANOVA COMPARING SBP RECORDINGS FOR CRUSHED AND INTACT

ADALAT @ PA .............................................................................................................. . 68 TABLE 29 - FIVE WAY ANOVA COMPARMG DBP RECORDMGS FOR CRUSHED AND INTACT

ADALAT 0 PA ...................................................................................................................... 70 TABLE 30 - FNE WAY ANOVA COMPARNG HEART RATE M E A S ~ M E N T S FOR CRUSHED AND

......................................................................................................... MTACT ADALAT @ PA 72 TABLE 3 1 - ~ & A N MAXIMUM, MINIMUM AND DIFFERENCE iN M A P DATA .................... .. ...... 73 TABLE 32 - F m WAY ANOVA COMPAR~NG MAPcRuSHm AND MAPtMArr ................................... 74

TABLE 33 - IN^- AND INTER-SUBJECT VARIABILITY FOR PARAMETER ESTIMATES AuCo,, CMAX. KA. TLAG, KE, TMAX, SBP, DBP, HR AND M A P ................................................... 75

TABLE 34 - SUMMARY OF VARIABLES REQUIRED FOR BIOEQUIVALENCE .................................... 76 TABLE 35- ANTIHYPERTENSIVE AGENTS FOR ACUTE HYPERTENSIVE E~L-IERGENCIES" .............. 1 0 1 TABLE 36 - IDEAL BODY WEIGHT BASED ON HE~GHT AND FRAME SlZE ................................ .... 104 TABLE 37 - NORMAL LABOMTORY TEST RANGES FOR SUNNYBROOK & WOMEN'S COLLEGE

HEALTH SCIENCE CENTER .......................................................................................... 105 TABLE 38 - DRUG CONCENTRATIONS (NGIML) FOR M E CRUSHED ADALAT @ PA FORMULATION

* ......................................................................... ............... ................................... I 16 TABLE 39 - DRUG CONCENTRATIONS (NG/ML) FOR THE INTACT ADALAT @ PA FORMULATION I 17 TABLE 40 - I N D ~ V ~ D L X L P ~ ~ A ~ ~ L I A C O K ~ N E ? ~ L " PAE~~~LIETCRS FOR !NTACT FORXIL'LAT~ON ....,...,.. 1 18 TABLE 41 - INDIVIDUAL PHARMACOKENETIC PARAMETERS FOR CRUSHED FOR~IULXTION ...,... 1 19 TABLE 42 - MAXIMUM, M ~ L M U M AND CHANGE IN PHARMACODYNAMIC PARAMETERS FOR

INTACT ADALAT @ PA ............................................................................................ 120 TABLE 43 - MAXIMUM. MINIMUM AND CHANGE IN P H A R ~ I A C O D Y ~ ~ ~ AM I C PARAMETERS FOR

CRUSHED ADALAT @ PA ........................ ......................................................................... . 12 1 TABLE 44 - PHARMACODYNAMIC PARAMETERS GROL~PED BY PHASE FOR T = O ...... ,,,., ........... , 122 TABLE 45 - MAXIMUM REDUCTION OF PHARMACODYNAMIC PARAMETERS GROUPED BY PHASE

.............................................................................................................................. 123

LIST OF FIGURES FIGURE I . STRUCTURE OF NIFEDIPINE .......................................................................................... 7 FIGURE 2 - METABOLIZATION OF NIFEDIPINE VIA P450 CYF 3A4 ............................................. 22 FIGURE 3 - PLASMA CONCENTRATION-TIME PROFILE OF CRUSHED AND INTACT ADALAT @O PA

TABLETS ............................................................................................................................... 41 FIGURE 4 . PLASMA CONCENTRATION-TIME PROFILE OF CRUSHED AND INTACT ADALAT @

PA TABLETS ON A LOGARITH~IIC ~ I S ................................................................................ 41 FIGURE 5 . COMPARISON OF AUCO-i2 BETWEEN CRUSHED AND INTACT ADALAT @ PA .............. 46

............... FIGURE 6 . COAIPARISON OF AuCo, BETWEEN CRUSHED AND INTACT ADALAT @ f A 46 FIGURE 7 . COMPARISON OF CMAX BETWEEN CRUSHED AND C TACT ADALAT @ PA .................. 49 FIGURE 8 . CONCENTRATION-TIME PROFILE FOR SUBJECT 19 ................................................ 6 1 FIGURE 9 - MEAN SYSTOLIC BLOOD PRESSURE READINGS OF CRUSHED AND INTACT ADALAT @

PA TXBLETS ......................................................................................................................... 67 FIGURE 10 - MAXIMUM AND MINIMUM SBPKT,, A N D SBPCRCsHED .............................................. 68

............ FIGURE 1 1 . MEAN DBP READINGS OF CRUSHED AND MTACT ADALAT @ PA TABLETS 69 FIGURE 12 . MAXIMUM AND MINIMUM DBPINTI\C- A N D DBPCRLISIIED ............................................. 70 FIGURE 13 . MEAN HEART RATE READINGS OF CRUSHED AND INTACT ADALAT @ PA TABLETS 71

........... F~GURE 14 . MEAN MAP READINGS OF CRUSHED A N D INTACT ADALAT @ PA TABLETS 74 FIGURE 15 - MEAN SBP VS MEAN CONCENTRATION OF N~FEDIPINE ........................................ 85 FIGURE 16 - MEAN DBP VS MEAN CONCENTRATION OF NIFEDIPINE ......................................... 87 FIGURE 17 . HR VS CONCENTRATION OF NIFEDIPINE ................................................................ 89

...................... FIGURE 18 . MAP VS CONCENTRATION OF NIFEDIPINE ................................. ....... 9 1

xii

APPEND~X A - ANTIHYPERTENSIVE AGENTS FOR ACUTE HYPERTENSIVE E~IERGENCIES ........... f 01 APPENDIX B - INFORMED CONSENT FORM ................................................................................. 102 APPENDIX C - IDEAL BODY WE~GHT BASED ON HEIGHT AND FRAME SlZE ................................ IO4 APPENDIX D - NORMAL LA~ORATORY TEST RANGES FOR SUNNYBROOK & WOMEN'S COLLEGE

HEALTH SCIENCE CENTER .............................................................................................. f OS APPENDIX E - CASE RECORD FORM ........................................................................................... 1 06 APPENDIX F - DRUG CONCENTRATIONS (NG/ML) FOR THE CRUSHED ADAL.~T @ PA

FOR~~ULATION ................................................................................................................... 1 16 APPENDIX G - DRUG CONCENTRAT~ONS (NG/ML) FOR THE INTACT ADALAT O PA FORIL~ULATION

.......................................................................................................................................... 117 ....... APPENDIX H - INDIVIDUAL PHAR~IACOKINETIC PARAMETERS FOR INTACT FORMULATION 1 1 8 ..... APPENDIX I - INDIVIDUAL PHARMACOKINETIC PARAMETERS FOR CRUSHED FOR~IULATION 11 9

APPENDIX J - MAXMJM, M~NIMUM AND CHANGE IN PHARMACODYNAMIC PARAMETERS FOR ........................... INTACT ADALAT @ PA ..................................... ,,. 1 30

APPENDIX K - MAXIMUM. M I N I ~ I U ~ ~ AND CHANGE iN PHARMACODYNA~LI~C PARAMETERS FOR

CRUSHED ADALAT @ PA .................................................................................................... 12 1 ................... APPENDIX L - PHARMACODYNAMIC P A R ~ ~ I E T E R S GROUPED BY PHASE FOR T = 0 122

APPENDIX M - MAXIMUM REDUCTION OF PHARMACODYNAMIC PAR.AMETERS GROL~PED BY

1.0 ~NTENT OF STUDY

Acute asyptomatic hypertension is associated with significant morbidity and rnortality.

The goal of therapy in acute hypertension is to provide a prompt and safe decrease in blood

pressure (BP) 1. A large number of clinically unstable patients with acute hypertension are

either intubated or have a nasogastric (NG) tube. Effective and immediate BP reduction in these

patients is generally accomplished by means of intravenous therapy. which is not usually

necessary and very expensive. Preferably. patients cari be treated with oral administration of

medications through the NG tube. Historically. nifedipine has been considered one of the drugs

of choice for the management of acute hypertension.

Nifedipine is a dihydropyridine calcium antagonist. and is comrnercially available in

Canada as an immediate release capsule (Adalat @) and sustained-release preparations (Adalat

b PA. Adalat @ XL). Althou&. the antihypertensive effects of ni fedipine are well established2.

preliminary studies and anecdotal evidence have led to the inappropriate. widespread use of

sublingual (SL) Adalat Q IR for the treatrnent of acute hypertension.

The shon acting Adalat @ IR capsule has been associated with sevenl cases of abrupt

and precipitous falls in BP and activation of the sympathetic nervous systernj. Activation of the

sympathetic nervous system. which depends not only on the drug but also on its

pharmacokinetics. has been associated with both acute coronary syndromes and heart failure. In

patients with myocardial ischemia a sudden fdl in BP results in a reflex tachycardia and a

reduction in coronary perfusion. producing a steal phenornenon and thus worsening ischemia.

Patients with an acute cerebrovascular incident may be put at risk of catastrophic strokes

following a sudden decrease in BP. indeed, numerous reports of serious. even fatal, adverse

events have been documented when oral nifedipine was administered acutely for the treatment

of severe acute hypertznsion4-7.

2

When the IR capsule is adrninistered SL. it is a common misconception that there is a

more rapid onset of action than oral administration of the nifedipine IR capsules. However. this

belief has never been supported by published pharmacokinetic or pharmacodynamie studies.

Rather. the absorption of SL nifedipine has been s h o w to be both negligible and erratic. and

any acute hypotensive response results frorn rapid absorption in the gaçtrointestinal tract80 9.

The pnctice of administering nifedipine sublingually has been questioned in the past 15

yearsl*-l 8. In 1985. the Cardio-rend Advisory Committee of the Food and Drug

.4dministntion (FDA) concluded that given the lack of outcome data and the serious adverse

effects. "the practice of SL nifedipine for hypertensive emergencies should be abandoned as it

was neither safe nor efficacious"~'! There has been no substantial outcome data since the

recommendation of the FDA in 1985 to support the use of SL nifedipine in acute asymptomatic

hypertensive emergencies or urgencies.

In cornparison with the rapid absorption of oral nifedipinr. the microcrystalline

formulation of nifedipinr PA (Adalat @ PA) tablets provides a more gradua1 and sustained onset

of action and may prove to be a suitable alternative for the treatment of acute asymptomatic

hypertension. In patients with mdignant hypertension. this slow-release formulation has proven

to be as safe and effective as initial monotherapy. without causing a precipitous fa11 in BP or

strokel? However. in hospitd. many patients that would benefit fiom Adalat @ PA may be

intubated or have a NG tube. Administration of the crushed Adalat (30 PA tablet is possible. but

there is a concern that crushing the PA tablet would effectively create an IR formulation and

therefore result in erratic absorption and a precipitous fa11 in BP. Unpublished information

suggests that the sustained-release properties of the Adalat Q PA tablet are retained following

crushing (personal communication, Bayer Canada).

The primary objective of this study was to compare the pharmacokinetic properties (rate

and extent of absorption) and the pharmacodynamic properties (magnitude and duntion of BP

reduction) of intact and crushed prolonged-action (PA) nifedipine tablets (Adalat @ PA) in

healthy. male volunteers.

This study sought to determine whether cmshed and intact nifedipine tablets meet the

criteria for bioequivalence in Canada.

The results of cornparing the pharmacokinetic and pharmacodynamic response of intact

and crushed nifedipine PA tablets rnay have important therapeutic implications. This study was

designed to determine whether cnishing the slow-mlease formulation of nifedipine PA tablets

would provide a predictabte and gradua1 reduction in BP. permitting its safe and potentiaily

cost-effective use in acute hypertension thereby avoiding the significant complications

associated with hypotension which may îùrther prolong a patient's hospitalization.

Furthemore. by avoiding the administration OF more expensive intnvenous medications in this

sening. the use of crushed nifedipine PA tablets will translate into direct drug cost-swings.

3.0 RESEARCH HYPOTHESIS

Crushing nifedipine PA (Adalat @ PA) tablets does not change the rate or extent of

nifedipine absorption and results in similar sustained-release pharmacodynamic (magnitude and

duration of BP reduction) and pharmacokinetic (rate and extent of absorption) properties as

intact tablets.

The Joint National Cornmittee on Detection. Evaluation and Treatmrnt of High Blood

Pressure has defined hypertension as "a diastolic blood pressure of 90 mm Hg or higher or a

systolic pressure of 140 mm Hg or higher based on the average olthree or more readings taken

at each of three or more visits over several weeks"z0.21. Table 1 on page 4 categorizes the

cnteria for the different stages of hypertension.

TABLE 1- CLASSIFIC~TION OF BLOOD PRESSURE FOR ADULTS AGED f 8 YEARS AND

O L D E R * ~ ~

Category Optimal? Normal Hi&-Normal Hypertension: Stage 1 Stage 2 Stage 3

Blood Pressure. mm Hg

Systolic Diastolic 4 2 0 and < 80 4 3 0 and < 85

130-139 or 85-89

*Not iaking antih~pertensivi: dru@ ruid not açutrly ill. Whcn systolic and diastolic blood prcssurcs faIl into ditkrent categoria. the hiphcr catrgory shoufd be selectcd to clûssif? the individual's BP status. For exmple. 160/92 mm Hg should be classitlsd as stage 2 h>~ertt.nsion . and 17U120 mm Hg should be classithxi as stage 3 hypertension. Isofiited systolic hypertension is detind as systolic BP 140 mm Hg or grmter and diastolic BP l e s than 90 mm tig and staged appropriately (cg. l7O/82 mm Hg is defincd as stage 2 isolatrd systolic hypencnsion). In addition to classifying stages of hypcrt~nsion on the buis of average BP levels. clinicians should speci. p m n c e or absence of t q r t organ diseitsc. and additional risk tàctors. This specificity is important tbr risk classitlcation and matment f Optimal BP with respect to cardiovriscular risk is lm than 120/80 mm Hg. tlowever. unusualIy low rcadings should be evduated for clinicai signiticance.

B& on the average of2 or more r a d i n e tiîka at mch of 2 or more visits d e r an initiai screening

Nifedipine is used in cases of acute asymptomatic hypertension. and hypertensive

urgency. Hypertensive urgencies are cases in which patients expenence markedly elevated BP

without severe symptoms or progressive target organ damage wherein the BP should be reduced

within hoursZ1. Oral agents are often used to reduce BP in such cases.

The etiology of approxirnately 95% of a11 hypertensive cases is still unknown21 and that

numbcr is evcn grcatcr xith regards to acutc xymptomritic hypertension. P r i r n q or idioprithic

hypertension stems from an unknown organic cause while secondary hypertension c m bi:

pinpointed to a speci tic source. Secondary hypertension can mise From renal disorders.

disorders of the centrai nervous systern. pheochromocytoma Cushing's syndrome. primary

hypenIdosteronism. endocrine diseases. or vascular disease. Correction of the underlying cause

of the hypertension will usually resolve the elevated BP.

Hypertension is usually an asyrnptomatic condition and treatment is usudly l i f e - l ~ n ~ ' ~ .

A report produced by Kowalski et al23 fiom the Cardiovascular Institute of the South round ihat

only 35 percent of those suffering hypertension are aware that they have it: only 49 percent of

those diagnosed with hi& BP are being treated for it: and only 2 1 percent of the nation's

hypertension victims are controlling the condition. There is another factor regarding patient

cornpliance resulting from one of hypertension's most dangerous characteristics: it is a Iife-

threatening condition with no symptoms. treated with medications. which often have side

eficts23. The Health Canada web page States that only one third of Canadians are aware of

their hypertension and even less are treating it properly24.

The primary goal in the treatment of hypertension is the reduction of BP. Initiai drug

therapy for the treatment of hypertension includes the use of diuretics or beta-blockers.

A list of recomrnended antihypertensive agents tor acute hypertensive emergencies is

available in the J N C - V I ~ O (Appendix A on page 10 1 ). It is important to note that the table in

the INC-VI is captioned with Wfedipine capsules not included nor indicated."lO

Sphygmomanometry has dways been an acurate and simple method of B P monitoring.

Now the pmper use of electronic manometers yields accurate and reproducible results.

Hoviever. mors in instruments. observer errors. subconscious bias and human error (Le.

posture) can give rise to erroneous conclusions. Posture and arm position can influence BP by

as much as 10 mm ~ $ 5 . huiety. meals. tobacco. alcohol. temperature changes. exertion and

pain are additional patient factors that cm alter the results of BP readings. Often. home BP

monitoring produces results that are lower than those measured at the doctor's office. These

higher readings found at the doctor's otlice are usudly caused by the anxiety of having to visit

the doctor and is called 'white coat syndrome' or 'office hypertension'.

Nifedipine is indicated in the treatrnent of essential hypertension and chronic stable

angina or effort-associated anginaZ6. Generally used in patients where beta-blockers and

liuretiss arc sontraindicaîed or incfictive. nifcdipinz is noi oRcn a first h é Jrug in tliè

treatment of hypertension. Figure 1 is the chernical structure of nifedipine.

Nifedipine is commercially available in Canada as a short acting immediate release (IR)

capsule (Adalat @ IR: 5 & 10 mg) and various sustained-release tablets (Adalat @ PA: 10 & 20

mg, Adalat @ XL: 20. 30 & 60 mg)26. Adalat CC. a sustained release tablet sold in the US. was

ranked 55" in total sales in the US market in 1999 with a total $376.676.000 retail dollars

sold27.

8

Nifedipine belongs to a class of antihypertensives called calcium channel inhibitors

(calcium channel blocker or calcium ion antagonist)26. Nifedipine is a Dihydropyridinr: a fom

of calcium channel blocker that acts as a vasodilator in cardiac and vascular smooth muscle,

4.2.2 MECHANISM OF ACTION

By inhibiting the transmembrane influx of calcium ions to pripheral vascular and

cardiac smooth muscles. nifedipine inhibits the contractile processes of the muscle that is

drpendent on extracellular calcium ions. This contractile inhibition leads to peripheral

vasodilation and consequently. a reduction in the peripheral vascular resistance. Calcium

inhibition is achieved through direct binding of nifedipine to voltage dependent and possibly

receptor operated dependent channels in the vascular smooth muscle. The artenal vasodilation

results in decreased vascular resistance and a direct reduction in BP.

4.2.3 PHARMACODYNAMICS

Oral administration of 10-20 mg of an intact nitédipine IR capsule results in the onset of

BP lowering effects within 1 O to 12 minutes. with a peak effect observed in 30 minutes. The

duration of action is estimated to be approximately 4 to 8 hours. When the IR capsule is

punctured and administered SL. the BP lowering effect is observed within 5 to 10 minutes. with

a peak effect observed in 30 minutes?

In cornparison, the PA tablet produces a much more gradual and prolonged

antihypertensive effect than the capsule. The BP lowering effect of an intact nifedipine PA

tabtet is observed within 30 to 60 minutes with peak effects in 1 to 3 hours. The sustained

release formulations also have a longer duration of action of 8 io 12 hours38.

9

Nifedipine 20 mg PA signif cantly iowered BP afler 1 houz9. Studies have shown that

there is a significant correlation between plasma nifedipine level and reduction in MAP but no

correlation between plasma nifedipine level and increased heart rate (HR)?

Kleinbloesem et ai reported that changes in SBP were srnail and not statistically

significant: while the DBP did decrease significantly. there was no ditrerence in BP reduction

between the capsule and table@.

4.2.4 PHARMACOKINETICS

4.2.4.1 ABSORPTIOIY/BIOA VA ILA BILIW

The absorption and distribution of nifedipine does not appear to be dose-dependent or

affected by prolonged administration. The effects of food on the pharmacokinetic protïlc

remains to be clearly defined. Sorne researchen have found an increase in Crnav and AUCa.lr

of the sustained release tablet with the ingestion of foodjl. Investiptors believe that bile

secretions and delayed gastnc emptying can play an important role in the disintegration and

absorption of the sustained release tablet.

The rnajority of the IR and PA tablets of nifedipine are absorbed in the jejunum. although

absorption is possible over the entire 1eng-h of the srnaIl intestine. Absolute bioavailability.

based on the recovery of a radiolabelled dose of nifedipine. mrasuring unchanged dmg and

metabolites. ranges between 60 and 70%32. The average bioavailability of ni fedipine observed

in studies is approximately 50%. However. reported bioavailabiiities for the Adalat @ PA tablet

between individuals range between 20.1 33 to 92%30. This di fference in bioavailability

accounts for a large inter-subject differences in plasma nifedipine concentrations34.

Tmax tirnes can Vary fiom 0.5 - 1 hour in the IR ~ a ~ s u l e s 3 ~ . In cornparison. peak plasma

levels with a nifedipine PA tablet are achieved in 1 to 4 hours.

4.2.4.2 D I S T R I B U T ~ N

Nifedipine is highly protein bound (92% - 98%). and has a particular affinity for

albumin. Forester et al has reported a mean steady state volume of distribution (Vdss) of

1.32 L/kg35. This suggests that nifedipine is distributed extensively in the tissues. Plasma

protein binding may be greatly reduced in patients with rend or hepatic impairment.

Nifedipine is extensively metabolized (30 - 40%) by first pass hepatic extraction to 3

pharmacologically inactive metabolites. The major metabolite is clrhycironijkriipine

(metabolite 1). produced by CYP 3A4 of the P450 system. which accounts for 50 to 60% of the

administered dose. A11 other metabolites dehydronifedipinic acid (metabolite I I ) . h y t i r q -

clrhylronifèdipineic wid (metabolite IIIa). and dehydronijidipinoiacm-ze (metabolite IHb) are

produced by CYP 3AJ and account for I O to 20% of the remaining metabolites. The three

metabolites are highly water-soluble and are excreted npidly in the urine. accounting for 60 to

80% of the administered dose. Less than 0.1 % of the dose can be recovered as unchanged drug

in the urine. The hydroxy and methoxycarboxylic acid derivatives accounts for approximately

95% of the metabolites excreted in the urine. The remainder is excreted in the feces in

metabolized form. most likely as a result of biliary excretion.

CYP 3A4 is genetically determined. and metabolism of nifedipine is bimodally

distributed into fast and slow metabolizen367 37. This contributes to the variability noticed

between subjects. It is also responsible for interactions noted with grapehit juice38.

itraconazole39 and ketaconazole. These interactions have also been noted with other

dihydropyridine calcium channel blockers. Early studies found an increase in the oral

bioavailability and plasma concentration of felodipine when grapehit juice was given shortly

11

before the adrninistered dose. Grapefruit juice is believed to suppress the CYP 3A4 enzyme of

the P-450 system and thereby inhibit the metabolism of nifedipine in the wall of the smail

intestine. This leads to diminished first pass metabolism and a greater bioavailability of the

drug available for absorption into the systemic circulation and an increase in the area under the

concentration-time curvej8. Some well-documented studies have exarnined the interaction

between dmgs and grapehit juice specifically regarding the inhibiting effects of CYP 3A4.

Dihydropyridine calcium channel antagonists arnlodipineJO. felodipine41. nicardipine.

nifedipine41-L)3. nitrendipineu+ 45. nosoldipine38. nimodipineJ6 have ail shown a significant

interaction with grapefmit juice. ~ ~ c l o s ~ o n n ~ ? carbamazepinej8. terazoçinJ2. lovastatin@

and buspironejO. have also been studied for interactions with grapehi t juice and have shown

elevated of drug concentrations and augmented thenpeutic and/or toxic etyects.

4.2.4.4 HALFLJFE (T%)

The initial t% of nifedipine following the administration of the IR capsule is 2.5 to 3

hous28 and a terminal half-life of 5 hours30. The t% of the sustained release XL formulation

varies fiom 4 to 16 hours depending on the formulation administered. The elimination t'/2 of the

Adalat @ PA tablet is approximately 2 to 4 hours2*.

FIGURE 2 - METABOLIZATION OF NIFEDIPINE VIA Pd50 CYP 3A4

De gmdatioa UV Ligbt

OOC

=- QRILIICI)

ight

Figure 2 is a diagram drtailing the metabolisrn ot'nikdipinr. via the PA50 -stem md degrdation ~fnifedipine under light. Yifcdipinc is brokcn do\cm to dch~droniti.dipinr: (metabolitc 1) undcr oxidativc dchydrogcniition luid cxposun: ta UV Iipht. Continucd cxposun: to light cm musc dchydronitkdipint. to losc an oxygcn from its NO2 group. Dehydronitkdipinic acid (rnctabolitc I I ) is formeri when thc COOCHI group in metabolitcl I is iittt'n'd to form ü crirboxylic ricici group. A furthcr aliphatic osidation of the CH, to Ct120tI in the hydroxy dchydroniîicdipinic acid dcrivativt: (mctabolitc Illa) is Iikrly to occur by wau of the livcr microsomal oxidation systcrn. Llndcr nsidic conditions. this mrtabolitr will hm a 3d ring cmt ing dehydronilkdipinolactone (metabolitc IIIb). Under rare conditions, hydroxylation rüid rc-cstrrisation cm crcatt: metabolite IIIb tiom metabolitc I.

TABLE 2- PHARMACOKINETIC PAEUMETERS AUC, CM=, TM-, T% AND f FOR NIFEDIPINE

FOUND IN THE LITERATURE

nia 200 0.5- 1 3-3 30-60 53 d a 60-80 - 3 4-6 3 0-60

GITS n/a 3040 5 -8 28 30-30

Ref 5 1

+ Fasting Light m d

* Hcavy m a i Y Sublingual administration : Bite and swallow g Grapchit juicr interaction study

Dose (mg)

20 Form

PA

54

9

AUC ( ~ i g n * h ~

300.1*146.4

PA IR IR' IR:

Cmax (ng/mi)

61.4k21.9

20

Tmax (hi

3

257.W77.4 nia nia d a

T% (hl 6-312.0

33.3* 19.1 107.&15.2 60.N7.4 88.4*1 t .O

F 4612 1

d a 25 (min,

33 (min)

25 (min)

d a nia nia d a

d a d a d a d a

4.2.5 TF~ERWEUTIC DOSE

Studies have shown that a 20 mg nifedipine PA tablet reduced BP similar to that of a

10 mg IR capsule, but the effect lasted twice as longZ9. 40 and 60 mg doses produced a larger

reduction in BP although 20 mg was suficient to achieve clinical effect?

4 plot o f the concentration-BP ciirw can detenine the minimum amounts of nikdipine

needed to reduce the BP a certain amount. Kleinbloesem et al have dernonstrated that

concentration is directly related to concentrations at the receptor site and therefore the nikdipine

concentration is correlated closely with the effects on DBP?

There is still some controversy as to the minimal plasma nifedipine concentration needed

to adequately reduce BP. Investigators have sugpsted that the lowest therapeutic plasma

concentration required to lower DBP by 10 mm Hg is l 5 ng/ml% while othen rnaintain that at

- - - least 25 ngml is necessaryD3- 39. Severity and urgency of the hypertensive state are important

considerations when determining the proper therapeutic dose.

4.2.6 SDE EFFECTS/ DRUG RELATED ADVERSE EFFECTS

Common side effects of nifedipine include. headache (7.3-7.9%). diviness (456.7%).

lightheadedness (6.7%), giddiness (6.7%), nausea (6.7%). vomiting (6.7%). gastrointestinal

distress (6.7%). flushing (5.8- 13.9%). heat sensation (5.8- 13 -9%). penpherd edema (3.747%).

hypotension (2.0% - IR only)l*. 58. and peripheral edema. In a study by Banzet et al. four of

eight patients complained of mild side effects while taking a single 20 mg dose of nifedipine.

including weakness. flushing and temporary headach&?

15

Interaction studies have shown that concomitant administration of cimetidine and

nifedipine inhibits the metabolism of nifedipine and thereby increases the oral bioavailability of

nifedipine6*.

IR nifedipine as available as a liquid filled capsule in which the nifedipine is dissolved in

polyethylene glycol and water. Sublingual administration of nifedipine requires that the

Adalat @ capsule be pierced and the liquid matrix be placed under the tongur. Absorption is

then believed to take place from the buccal cavity. Similar to this method is the bite and

swallow method of administration. where the Adalat @ capsule is chewed by the patient and

then swallowed. It is widely believed that the liquid nifedipine IR Formulation will be

completely and rapidly absorbed from either the buccal mucosa or GI tract. quickly reducing

elevated BP without the expensive cost or the time-consuming task of an I.V. administered drug.

Anecdotal evidence suçgests that. even today. SL nifedipine is used extensively for the

treatment of acute hypertensive emergencies and urgencies. However. SL administration of

nifedipine has corne under some scrutiny over the past decade and its safety has been

debatedlo-18. In 1985 the Food and Drug Administration concluded that due to the risk of an

abrupt and precipitous fa11 in BP. 'rhe practice of SL nifedipine for hypertensive rmergencies

should be abandoned as it is neither safe nor efficacious"lJ. Cases of cerebrovascular ischemia

moke. acute MI. conduction disturbances. fetal distress, and even death have been reported with

the use of sublingual nifedipine3.

A review of the literature finds little or no evidence that the safety and eficacy of an IR

nifedipine intervention has been established. In the absence of outcome data establishing

16

benefits. if any, even one fatality must be considered too many15. In fact. adverse reactions

have been reported as far back as 1978.

Contrary to what physicians believe. published reports indicate that the BP reduction is

rapid and unpredictable with SL administration of nifedipine. Often. cases of uncontrolled and

profound hypotension. peripheral vasodilation. steal phenornenon. reflex tachycardia and

excessive catecholamine release have been reported atier such administration. Messerli clearly

points out that the sublingual use of IR nifedipine hm never been approved for the treatrnent of

any form of hypertension. includinp emergent hypertension 15.

With the lack of standardized methods of administration. the vwiability from one

administrator to the next is significant and the variability between patients rven greater. Van

Harten and his colleagues found that SL absorption of nifedipine was negligible and variable

from the buccal mucosas. The apparent response observed with both the SL and the bite and

swallow methods of administrations resultrd riom the ingestion of the nifedipine liquid and the

subsequent absorption of the drug from the GI tract.

Elliot states. "it has become increasingly apparent that the capsule formulation of

nifedipine is disadvantageous.. . by its short duntion of action and the requirement for multiple

daily administration.. .'*j3.

Adalat @ PA is a 'Prolonged Action' formulation. However. given the reported

concentration-tirne profile with a Tmau of approximately 2 hours and a half-life of

approximately 4 hours. this formulation may not be a sustained release product. Nevertheless.

tliere was concem tliat crusliing a PX iabld mi& produse unprediciablè results 5irnila.r ti> those

found with the Adalat @ oral capsule.

Cnishing tablets is often the only method of administration of solid ocal dosage forms to

patients on nasogastric suction. Crushing an immediate release tablet will often only minimally

change the phmacokinetic characteristics of a medication. The safety of crushing slow release

formulations has oflen been questioned due to the possibility that the rntire dosage might be

released and absorbed immediately .

Only two studies have reported the pharmacokinetics of a drug before and aAer crushing

an immediate release tablet. In 1992. Lubowski et a161 conducted a study with the immediate

release temafloxacin tablet. using bioequivalence criteria to substantiate therapeutic

equivalence. Crushing increased the AUC by 13%. and the Cmêu of temtloxacin occurred

earlier ( 1.19 hours venus 3.33 hours) and was 22% greater compared to the intact tablet.

Lubowski points out that plasma concentrations of both crushed and intact temdoxacin were

adequate to reach therapeutic levels to treat itirections. While the study demonstrated that the

crushed and intact tablets were not bioequivalent. no direct measure of rate (ka or CrndAUC)

was calculated,

Vincent et a162 observed similar results when trovafloxacin was crushed and

administered via a NG tube. The 90% confidence interval for AuCa, between crushed and

intact treatrnents were well within the criteria for bioequivalence (ratio: 100 and 90% CI: 9 1.3 -

18

109.5%). indicating a similar extent of absorption. Vincent claimed that his findings

demonstrated interchangeability between the two dosage forms. but Cmax was 1 1% larger and

occurred earlier (, 1 . 1 hours versus 1.7 hours) for the crushed tablet. Again. no direct rneasure of

rate was reported.

Beginning with compulsory licensing in 196% copies of innovator's formulations of a

drug were legal in Canada. However. as copies. to ensure equivalent therapeutic response. and

possibly in response to reports of diffenng responses between innovator and copied formulation.

bioequivalence testine - became and has remained an important part of the development of

generic formulations.

Generic dmgs, are internationally called interchangeable multi-source pharmaceutical

products. In Canada. and in rnany other countries. a bioequivalent designation is made when

both the rate and extent of the generic formulation is shown to be similar to the innovator

product. according to regulatory citena. By extension. rnany jurisdictions accept bioequivalent

products as interchangeable.

Two medicinal products are bioequivalent if they are pharmaceutically

equivalent and if their bioavailabilities (rate and extent of absorption) aRer

administration in the same molar dose are similar to such a degree that their effects. with

respect to both efficacy and safety. will be essentially the same63.

The Health Protection Branch (HPB) of Health and Welfare Canada has provided a dmgs

directorate guideline entitled. The Conduct and Anaiysis of Bioavailability and Bioequivaience

Studies. which details step by step guidelines for conducting a bioavailability or bioequivalence

study*.

Bioequivalence is a measure of the rate. judged by the Cmaw. and extent (calculated

from the AUC) of absorption of the therapeutic agent from a drug formulation. One c m

measure these pharmacokinetic parameters fiom the concentration-time profile derived from

penodic blood sampling and analysis of the dmg Crom the systemic circulation. To achieve

20

bioequivalence a test product must exhibit similar phannacokinetic characteristics ~vith respect

to rate and extent of absorption.

Agencies reguiating the release of genenc dmgs have facilitated generic New Drug

Application (NDA) procedures by requiring a pivotal bioequivalence study to demonstrate that

the genenc fornullition is fùlly interchangeable with the innovator product63. The innovator

product's safety and eficacy profile is adopted for the generic product if it found to be

bioequivalent. Therefore. bioequivalence is generally the most important proof to substantiate

therapeutic equivalence between a brand narne and a generic product.

Comparative bioavailabiiity (EQUATION 1) is a usehl tool when detennining which of 2

formulations hm a greater extent of absorption.

.i UC, CL,, DoseH F = EQUAT~ON t

Dose,, il W H -CL,

When conducting a two-way. cross-over bioequivalence study. 2 assurnptions can be

made: ( I ) since the study is a two-way study using the sarne individual for both study days. it is

n a W to assume that. on average. the clearance remains the same (CL..* = CLs). (2) The dose

will be the same for both study days (Dosee4 = Dosee). Under these assumptions. the above

equation simplifies to:

rtiere is an inherent problem with making these assurnptions. While it is easy to ensure

that the dose remains the same. we have to assume that the clearance is equal as well. Making

this assumption with an individual can be dificult for dmgs that are 80w dependent or where

rend clearance is influenced by p ~ 6 3 . However. in a group of individuals. it is reasonable to

assume that the average clearance for each formulation is sirnilar.

The area under the concentration-time curve is used to rneasure the extent of absorption.

Using a mathematical trapezoidal rule one can calculate the area under the concentration-time

curve up to time t.

Additionally. EQUATION 4 cm estimate the area from the last known concentration (Ci,[)

io time intinity.

When assessing bioequivalence the HPB requires that the ratio. AUC,,JAUC,fe,n,, and

the accompanyiny 90% confidence interval between the generic test product and innovator's

reference product must faIl completely within a 0.8 to 1.25 (80 to 125%) boundaq6'! to be

designated as bioequivalent.

Cmau is an indirect measurement of the rate of absorption. The highest point on the

concentration-time curve represents the maximum concentration. In Canada. the average Cmav

test to reference ratio (Cmau,,t/Cmau,g,,,) between the generic test product and innovator's

reference product must faIl within a 0.8 to 1.25 (80 to 125%) boundary to meet the HBP criteria

for bioequivalence64. In the U.S.. the FDA requires that the 90% CI must lie between an 80 to

125% boundary.

It is important to note that bioequivalence may not dictate therapeutic equivalence. In

fact while bioequivalence indicates that the phmacokinetic properties between the innovator

dmg and the generic form are similar. there is no requirement that the therapeutic effect of the

test and reference products be compared. It is simply implied that the generic dmg. because it

uses the sarne active moiety. with the same rate of absorption and same extent of absorption.

will 'act' the same way in the body as the innovator h g . For a test product to establish

therapeutic equivalence. it must also show the same eficacy and safety clinically as the already

proven reference drug.

Bioequivalence studies use a very simple randomized. two-penod. hvo-treatment. two-

sequence. cross-over design. Subjects receive each formulation. separated by a suitable washout

period in a mndomized order and have senal blood sample drawn over 3 to 4 haif lives in

suitable tiequency to properly categorize both absorption and elimination of each formulation.

Inclusion and exclusion critena are prepared in an attempt to create a homogeneous

study population. Age. weight. height. sex and ethnicity are considered and relevant variables

include or exciude volunteers from participating in the study. Baseline characteristics. usually

detemined from a medical physical. are used to evaluate whether subjects are suitable for the

study. Al1 of these precautionary measures are developed pnor to the initiation of the study in

an attempt to minimize overall variability.

Plasma samples are generally used to acquire drug levels fiom the systemic circulation

although some studies may require the collection of urine. feces. hair. sweat or breath to

accurately evaluate dnig levels in vivo. it is often valuable to know the metabolite or

metabolites of the drug in vivo. Determining the arnount and/or structure of the metabolite(s)

c m be a good indicaior if itlthey will interfere with dmg analysis or whether itlthey are active or

inactive.

Statistical procedures aid in designing a bioequivalence study. Sample size calculations

are encouraged to adequately power the study . Intra and inter-scbject variability are important

considerations when designing clinicd trials.

Bioequivalence studies are dificult to conduct on dmgs with an invinsically large

hm-subject variability (e.g. buspirone). In some cases large sarnple populations are required

23

for adequate power to demonstrate bioequivalence. However, large sarnple sizes increase the

cost and difficulty ofconducting a study. As well. an ethics comrnittee rnay be hesitant to

approve a study. which requires a large nurnber of subjects to take a cimg with a narrow

thempeutic range. In such cases the rules can be altered slightly in an attempt to make the study

safè yet effective. A part prospective and part retrospective study could be created to acquire

die necessary subjects. Aiso. a smaller sampie size may 'be used and the SU% confidence

interval or the 0.8 to 1.25 boundary of the study rnay be altered to allow the dnig to be critically

evaiuated without introducing unnecessary risk to the sarnple population.

Bioequivalence studies are subject to modification in circumstances that require special

consideration. Modified Release Formulations ( M W ) are products which delay. extend. or alter

the release of the therapeutic substance from a conventional formulation. A comparative

bioavailability study evaluating the MRF and the conventional fomulation will not produce

similar Cm, and AUC profiles and therefore will not be bioequivalent. Thus. bioequivalence

studies are inappropriate when comparing immediate release formulations with the associated

MRF.

Prodmgs. where the active metabolite is the moiety of interest @.p. L-Dopa or ASA).

must be studied fiom a simiiar prodrug. It is possible to compare the same active metabolite

derived from two different prodrugs. In this case the rate and extent of absorption may be

different. leading to the conclusion that the drugs are bio-inequivalent63.

The results of this snidy may have important thenpeutic implications. It has been well

documented that short-acting calcium channel blockers are associated with significant adverse

events and should not be used in unstable clinical situations. such as acute asymptornatic

hypertension. A large number of clinically unstable patients with acute asymptomatic

hypertension often have a NG tube. necessitating the crushing of oral medications. This study

will determine whether crushing the slow-release formulation of nifedipine PA tablets wi 11

provide a predictable and gradua1 reduction in BP. thereby avoiding the significant

complications associated with hypotension which may further prolong a patient's

hospitalization. Furthemore. by avoiding the administration of more expensive intnvenous

medications with acute asymptomatic hypertension. the use of crushed ni fedipine PA tablets

will translate into direct dmg cost-savings.

5.0 METHODS

5.1 STUDY PROTOCOL

5. f .l BASIC STUDY DESIGN

This was an open-label. randomized. NO-treatment. two-sequence. two-phase. crossover

study of two 12-hou treatment periods separated by a minimum three-day drug-fiee washout

period. An open label study was required due to the method of drug administration.

5.1.2 STUDY POPULATION

The study population consisted of normal. healthy. male volunteers. Volunteers were enrolled

after giving informed written consent (Appendix B) prior to a medical rxam and labontory

tests. Subjects were required to complete and pass both a medical physical and baseline

hematological labontory test to be considered for the study.

5.1.3 INCLUSION CRITERIA

Criteria for entry into the study included:

Nonsmoking male subjects between 18 and 50 years of age.

Written inforrned consent obtained prior to commencing the study.

Completion of a successful physical exam by a qualified physician. including pst

medical histoy. allergies tu medication. HEENT. pulmonary. cardiovascular.

gastrointestinal. neurological. musculoskeletal. genitourinary and skin examination.

Receive a 1 Nead electrocardiograrn (ECG) and approved normal by cardiologist.

Pass hematology tests including sodium (Na3, potassium (K3. chloride (CI-), carbon

dioxide (CO?). magnesium (Mg?, calcium (Ca?. phosphate (PO4-'). mdom serum

glucose. AST and ALT liver profile, serum creatinine and urea rend profile. s e m

26

albumin. CBC and differential. Al1 tests being within the normaVreference ranges

(Appendix D - Normal Laboratory Test Ranges for Sunnybrook & Women's College

Health Science Center)

6) Subjects not receiving any prescription or non-prescription medication for at Ieast 30

days prior to the initial baseline physical. and willing to avoid any medication. for the

rcmaiiiiicr of the siudy; and avoid caffèiiiè. alcahol aiid grapefruit juicr for 48 prior aiid

throughout the study.

7) Subjects with normal BP (a diastolic BP of 5 95 mm Hg or less) measured standing and

supine.

Criteria which would exclude subjects. are:

1 ) A history of hypertension.

2 Fainting or diviness when exposed to needles.

3) Known or suspected history of significant gastrointestinal disorders.

4) Subject has experienced or may experience adverse events with nifedipine.

5 ) Weight > 15% of ideal based on fiame size.

6) History of substance or alcohol use.

7) If the subject is expected to require the use of a systemic antimicrobial agent during the

course of the study.

8) The subject is known or suspected to be unable to comply with the study protocol or

medication schedde.

5.2 RESEARCH PROCEDURE

5.2.1 BASELINE S ~ Y PROCEDURE

5.2.1.1 PATIENTPHYSIC~IL

Subjects were required to attend and pass a rnedical physical administered by a qualified

physician to continuc in thc study. n i c physical includcd hcight. wciglt. ps t mcdical histor;.

allergies to medication. HEENT. pulmonary. cardiovascular. gastrointestinal. neurological.

musculoskeletal. genitounnary and skin examination. BP (standing and supine) and a 17-lead

ECG,

Hematological laboratory tests included sodium (Na3. potassium (K3. chloride (Cl-).

carbon dioxide (CO?). magnesium ( ~ g 7 . calcium (Ca-) . phosphate (Po4-). randorn semm

glucose. AST and ALT liver profile. serum creatinine and urea rend profile (BLTN). serum

albumin. CBC and differential. Al1 tests were considered valid if they were within 10% of ihe

nonnal/reference ranges in use at Sunnybrook and Wornen's College Health Science Center rit

the time of study.

5.2.2 STUDY DAY PROCEDURE

Subjects were randomly assigned to receive intact 20 mg (2 x 10 mg) Adalat @ PA or

crushed 20 mg (2 x 10 mg) Adalat @ PA. Subjects were instructed to:

(i) abstain from caffeine. grapefruit juice, and alcoholic beverages for 48 hours prior to each

treatment period and throughout the study day.

(ii) fast starting at 2200 H the evening pnor to the study day and remain in a fasting state for

four hours after the first dose of the study day, with access to water only. A

28

xanthene-fiee lunch and dimer was allowed 4 hours and 10 hours pst-dosing,

respectively.

(iii) remain seated or supine For the fint four hours.

On each study day. subjects arrived at the designated study center at which time an

indwelling venous catheter was inserted in the forearm. The same a m was used for blood draw

on both stuciy days unirss a suitabir vein was not riccessiblt: in that m. Aller a 10 minute r d .

a baseline blood sample was collected and BP and HR were measured before the moming dose.

Volunteers then received a single. oral dose (with 150 ml of water) of çither: (i) intact

nifedipine PA tablet 2 x I O mg or (ii) crushed nifedipine PA tablet 2 x 1 O mg.

5.2.3 PTLL CRUSHLNG

Nifedipine was administered as an oral dose consisting ot'hvo Adalat BI PA I O mg

(Lot: BBFST) tablets purchased from AG Bayer. Canada. Dunng the crushed phase. both

tablets were crushed in a mortar with a pestle for approximately 10 seconds under subdued light.

The pestle was rinsed with a small arnount of water to remove al1 of the nifedipine. Portions of

150 ml of water were added to the crushed sample md the subject was asked to drink the

crushed tablet and water mixture directly tiom the mortar. until al1 150 ml of water was

consumed. Steps such as swirling the water. rinsing the sides of the mortar. and inspecting the

mortar for any remaining yellow powder were taken to ensure that al1 nifedipine was ingested.

In dl cases. oniy 150 ml of water was required.

5-2-4 BLOOD PRESSURE/HEART RATE MEASUREMENTS

BP and HR measurements were completed. in triplicate. at tirne zero and approximately

2-3 minutes following each blood senim sample using a portable automatcd BP device

(Omron HEM-705-CP SN#21700089536). The average of the three rneasurements was usrd in

statistical analy sis.

Blood samples (10 ml in volume from an indwelling antecubital venous catheter) were

collected at times corresponding to 15.30. and 45 minutes and 1. 1.33. 1.67.2.2.5.3.4 6.8.

10, and 12 hours following the moming dose. Due to the known instability of nifedipine to

light. al1 procedures were carried out under subdued light and al1 blood collection tubes were

wrapped in aiuminum foil. The saline was removed and discarded from the P R N adapter pnor

to the 10 ml blood dnw. 10 ml of blood was then removed by syringe and placed directly into a

10 ml green top heparh filled tube (Vacutainer). Following sampling the P R N adapter was

tlushed with saline to maintain catheter patency. A heparin-saline solution was used to avoid

clots. in the PRN adapter. in patients where clots began to fom. PRN adapters were replaced in

subjects where irremovable dots formed. Blood samples were stored on ice in a dark

refrigerator until centrifuged and separated (approximately 1 hour). Harvested plasma samples

were subsequently fiozen at -20°C until andysis. Afier the 12 hour blood sample. IV catheten

were removed and discarded. The IV site was cleaned and bandaged and upon scheduling of

snidy day 2. subjects were sent home.

S e m samples were sent to AG Bayer in Wupertal. Germany for anaiysis. The method

used to anal. the serum samples is similar to the gas chrornatographic method with electron

capture detection described by Ramsch et a@.

The extraction procedure consisted ofmixing 0.5 ml of plasma with 1 ml of toluene.

containing 50 ngml of the intemal standard and 50 pl ofa 0.5 M NaOH solution in a 3 ml

autosampler bonle for 5 minutes. The boales were transfened directly into the autosampler.

without centrifugation. The autosarnpler syringe was set to exüact 2 p1 from the top l /3 of the

bottle. The injector and detector temperatures were 250UC and 3OO0C respectively. The initial

tempenture (splitter closed) was 160°C and 1 minute aAer injection the splittrr was open and

the tempenture prograrn was started at 10°C per minute. The final temperature. 77OUC. was

reached in 12 minutes and the duration of analysis was 32 minutes.

Lirnit of detection is as low as 1 nglml. The CV of the assay is 9.7% at 2.6 ng/ml. 2.5%

at 22 @ml. and 4% at 84 ng/ml. Analytical run performance data and statistics (standard curve.

QCs etc ...) were not provided by AG Bayer and are therefore not presented.

This study was designed to test whether cmshed and intact nifedipine tablets are

bioequivalent. To demonstrate bioequivalence. the phmacokinetic rate (Cmau) and extent

( W C ) of absorption between crushed and intact nifedipine (Adalat @ PA) tab!ets muçt be

similar according to the guidelines provided by Health Canada. However. since Cmav is not a

direct measure of rate. ka and CmadAUC values were usrd to rvaluate the rate of absorption

between the test and reference treatments.

Individual serum concentration-time pro tiles were plotted and used to determine peak

semm concentration (Crna) and time of peak semm concentration (Tmax). The log Iinear

tmpezoidal nile was used to determine area under the concentration-time curve (AUC) from

time zero to 720 minutes (AuCo-[). The area From time Ti, to infinity

(AUCnîri4) was determined using the last known concentration (Ci,,) divided by the

elimination rate constant (CiWt/ke). Ke was determined fiom siope of the terminal phase of the

log transformed concentration-time profile of individual subject data enswing a minimum of 3

points and a maximum of 6. Choice was based on greatest correlation coefficient. Adding these

two areas (AuCo.[ and AUCn,,,) resulted in an estimation of the area under the concentration-

time curve front time zero (O) to infiinity (AuCo.,). AUC for nifedipine is reported in ng*h/rnl

because al1 values in the literature were reported with this convention.

initial estimates of the elimination rate constant (ke) were determined by linear

regression of the terminal phase of the serum nifedipine concentration-time profile assurning a

one cornparmient model. initial estimates of the absorption rate constant (ka) were determined

32

by the method of residuals. Ka and Tlag values used in analysis were determined using the

WinNonlin computer prograrn based on either and one or two compartment model. and

determined by which value had the lower AIC nurnber. Using the highest value of the

concentration-time profile and dividing that value by that subject's AUCo, determined the

CmadAUC value. Half-life (t %) was calculated using the slope of the terminal phase of the

tiniz-concentratio s w e . i-ldf-life is reporteci in minutes.

Individual concentration-time profiles were also analyzed using the WinNonlin computer

program for estimates of ka. ke. AUC. Tlag. Cmax. Tmav and half life. The Akaike Information

Criteria (AIC) and Schwartz Criteria (SC) were calculated by WinNonlin and used to determine

goodness of fit between one and two compartment modeling with and without lag times.

The ptimaty pharmacodynamic outcome includes providing data to support the daim

that the pharmacodynamic effects of cnished and intact nifedipine (Adalat @O PA) tablets are not

clinicail y or statistically different. SBP. DBP. mean artenal pressure (MAP) and HR rnust not

be clinically or statistically different brtween the crushed and intact ni fedipine (Adalat 0 PA)

tablets.

5.3.4 PILARMACODYNAMIC ANALYSIS

5.3.4.1 BMOD PRESSURE%HEA RT RA TE IME~~SUREMENTS

BP measurements were recorded in triplicate. Reported values are the mean of the three

systolic values over the mean of the three diastolic values. Maximum BP reduction was taken

using the initial BP reading time zero (0) and subtncting the lowest BP reading within the first

180 minutes (fint 10 serum sarnples).

Five way ANOVA blocking for subject sequence. period bmulation. and time was also

carried out on the log transformed pharmacodynamic parameters of SBP. DBP. MAP and HR.

MAP was calculated using the following equation.

:M P = DB P + & Pulse ~r essure)

i W P = DBP + ~ ~ ( s P B - DBP)]

Review of the Iiterature for Nfedipine phmnacokinetic parameters (AUC and Cm,)

revealed that the average intra-subject variability (CV%) varied between 15 to 35%. Assuming

an intra-subject variability of ranging between 15 and 35%. a difference varying from 20 to 30%

and setting a = 0.05 and P = 0.20. will yield sarnple sizes s h o w in TABLE 3 (below) based on

the formula published by Stolley and ~ t r o r n ~ ~ .

TABLE 3 - S ~ I P L E SIZE CALCULATIONS BASED ON INTRI-SUBJECT VARIAB~LITY AND MEAN DIFFERENCE

1 % Diffeerence

Altematively. a sample size calculation based on the 90% CI of log transformed AUC

and Cma.. assuming an intra-subject variability oF20%. with a deviation of 5% or less. and

setting a = 0.05. p = 0.20. predicts that 20 subjects are required if the 90% CI are to faIl

completely between 80 to 125%67.

Therefore. 20 subjects are recornrnrnded for the study based on the combined sample

size estimations of stolley66 and ~ i l e t t i ~ ~ .

Means are reported * the standard deviation (rnean * SD). The computer program

WinNonlin was used to calculate al1 analyses of variance (ANOVA) tables and to calculate the

tcst to rekrcncc ratios and dicir individual 90?6 confidence intervals. Four way A N O U was

completed for each ofthe naturally log transformed pharmacokinetic parameters: AUC and

Cm=. Tlag. ka and ke. Tmax was not log transfonned but analyzed in the same manner.

ANOVA blocked for sequence. subject. period and formulation and for the pharmacodynamie

data time was also included. Al1 data was weighed equally.

The five percent level was used as the limit for statistical significance (ix. p < 0.05). Al1

subsequent reference to significance will refer to this level.

The standard criteria for Dixon's Test and the T Procedure were rmployed. Based on a

sample size of 2 1. Dixon's Test states that. if r > 0.450 the tested value is considered

significantly different. Based on a sample size ot'21. the T Procedure states that. Tn > 2.733 the

tested value is considered significantly different.

The Fisher's Protected Least Significant Difference (LSD) was calculated for ANOVA

variables with significant p values that were believed to be tmly insignificant. This LSD

represents the significant difference that can detected by the parameter evaluated with ANOVA.

Equation 6 is used to calculate the LSD.

inter- and uitra-subject variables were calculated using data acquired from WinNonlin

eenented ANOVA tables using equations 7 and 8. Inter- and intra-subject CV calculations are L

presented with each ANOVA table.

inter - strbjecr C V = 1 00 x ~tlSResidual(Seq) - ~bISResidua1 3

EQUATION 8 -

To demonstrate bioequivalence in Canada the relative ratio and the 90% contidence

interval for relative ratio of AUCcmidAUCinwc< must faIl complrtely within an 80-1 25%

boundary. The relative ratio of C m a ~ , ~ , ~ c ~ ~ ~ ~ , , , ~ must also faIl within the 80- 125%

boundaq. Only if both of these critena are met is the test product (crushrd Adalat (8 PA)

considered bioequivalent with the reference product (intact Adalat @ PA). nie foollowing

calculations detail the procedure used to calculate the relative ratio and the upper and

lower 90% CI.

m e ethics conunittee at Sunnybrook and Women's College Health Science Center

approved the study protocol on Febniary 1". 1999.

76 non smoking. hedthy. maie volunteen were enrolled in the study by phone cal1

between February 1''. 2000 and December 1". 2000. 2 volunteers did not meet the study cnteria

and 3 volunteers were lost to Follow-up. This left 21 volunteers to complete the study protocol.

Al1 subjects were selected because they meet al1 inclusion critena including negative past

medical history. a normal physical examination and normal routine laboratory and ECG test.

6.3 DEMOGRAPHICS

The 21 subjects had a mean * SD age of 30 * 8.2 (rang 1849) years. body weight of

80.8 12.1 (range 61 -1 06) kg. and height of 178.1 * 5.9 (range 167- 19 1 ) cm. Table 4 Iists the

individual subject age. height. weight and baseline characteristics at the time of physical

assessment. Al1 subjects were within f 15% of ideal body weight based on height and Frame

size,

TABLE 4 - INDIVIDUAL SUBJECT HEIGHT, WEICHT, ACE, SBP, DBP, MAP AND HR AT THE TIME OF PHYSICAL ASSESSMENT

Su bject

1 2 3 4 5 6 7 8

Table 5 outlines the mean pharmacodynamie data based on the physical examination.

Max Min

TABLE 5 - SUMMARY OF THE MEAN PHARMACODYNAMIC DATA SBP, DBP, MAP AND HR FOR 21 SUBJECTS BASED ON INITIAL PHYSICAL

Height (cm) 178 177 178 175 173 i 70 171 170

191 169

Supine 1 124.4* 13.4 1 74.618.6 / 91.2*9.4 1 67.3 * 7.3

With 21 subjects and 30 blood samples over two study phases, 630 blood samples were

drawn in total. 2 samples were not included in the study analysis. 1 sample was missed during

blood sampling and 1 was misplaced/lost during transport to Gemany.

Weight (kg) 85.8 61 89.9 7 8 65 63.5 71 64

Standing

1 06 61

Age (years)

24 28 28 25 23 i 8 3 3 38

Systolic (mm Ha)

124.2 * 12.8

49 18

Diastolic (mm Hg)

72.8 7.8

Standing

102 1 56

SBP (rnrnHg) 120 110 124 133 136 i OZ 132 138

Supine

MAP (mm Hg)

89.9 * 8.2

SBP (mmHg) 118 1 08 128 118 1 22 i i4 142 1 46

54 92

HR (BPM)

-

DBP (mmHg)

66 54 74 74 7 4 O0 73 78

MAP (mmtfg) 84.0 72.7 90.7 90.0 91.3 78.0 93 -3 98.0

DBP (mmHg)

66

84.0 1 10.0

MAP (mmttg)

83.3

1 06 1 56

HR (BPM) 60 64 63 77 65 76 66 72

54 74

5 4 96

72.0 92.0

833 1 16.0

71 1 87.3

52 80

76 00 74 84

9 1.3 82.0 96.7 104.7

Individual dnig concentrations for both crushed and intact Addat Q PA tablets are

presented in Table 38 and Table 39 (in Appendix F and Appendix G on page 1 16 and 1 17.

respectively). individual pharmacokinetic data is presented in Table 40 and Table 41 in

Ao~endix . . H and Appendix 1 on pages 1 18 and 1 19. respectively. The mean pharmacokinetic

parameter estimates for AUCoi2. AuCo,. AUC Ratio (%). Cmax (ng/ml). Tmav (min). Tlag

(min). ka (min"). ke (min-') for both intact and crushed formulations are presented in Table 6.

S e m concentration profiles varîed extensively among subjects and this are reflected in the SD.

TABLE 6 - COMPARISON OF THE PHARMACOKINETIC PARMETERS OF CRUSHED AXD INTACT ADALAT @ PA TABLETS

AUC(J.~ 2/AUCo.aD 1 87.2 ratio (%)

1 89.6

Cmax (nglrnL) ( 3 1.7 t 14.4 1 JO. 1 I 13.9

Tmax (min) 1 1 1 1.7 f 53.9 1 95.8 f 45.1

ke (min-') 0.0054 I 0.0060 + 1 0.0015 1 0.0016

1 Ceometrie

Figure 3 on page 41 presents a graph of the mean concentration-time profile for the

crushed and intact Adalat @ PA tablets. Figure 4 on page 4 1 presents the sarne plasma

concentration-tirne profile on a Logarithmic axis. Blue diamonds in the chart represent the mean

40

concentrations of the crushed formulation while red squares depict the mean concentrations of

the intact formulation. These symbols. blue diarnonds for crushed and red squares for intact.

will be used throughout this thesis.

It is important to note that the gnph is a representation of the mean data and therefore the

highest observed concentration in the rnean profile is lower than the maximum Cmax reported in

Table 6 and Table i 1. This is bisaux the mran value olali concentmiions &hm iime point i20

minutes (Crnax,-mh,d in graph) will be equal to the value in the p p h . However. al1 individual

C m a ~ values did not occur not at 120 minutes and. therefore. the Cmav values presented in

Table 6 and Table 1 I will not be equivalent to the highest observed concentration in the graph.

The same is tnie for al1 pharmacokinetic parameters that are evaluated %om the plasma

concentration-time profile. It is apparent from this graph that concentrations for the crushed

tablet are on average higher than concentrations observed for the intact tablet.

FIGURE 3 - PLASMA CONCENTRATION-TIME PROFILE OF CRUSHED AND INTACT ADMAT @ PA TABLETS

O 200 400 600 & Crushed

Time (minutes) - - l- - Intact

Figure 3 depicts ihe plrisrna conccntmion-timr protïle of crushed (bluc dimonds; solid lincl rind intact ( r d squares; dottrd tint!!] nitkdipinc PA in hdthy. mals voluntetrs. Concentration (y-mis) is maured in nghl ;in4 timr (x-xuisi is msiurttd in minutes, 'The plasma concentraiion of both intact and crushed nifedipinc i n m c s npidly during the initial 100 minuits. T h plstmu n w 100 minurei indicata the rippronimare C m a d md Cmw,, vducs. It is dm h m the p p h ihru Ihe crushed nifcdipine rrichcs a higher ma~imum concrnuarion sin3 that thc t\UCIbi2 and AUC,r, will bc gmtct than the inixt formufation. Slopcs of the tcnninal phase of the drug (aflcr 100 minutes) arc similrir: indicarhg die r.liminaiion of cach funulation is similar.

I I I

200 400 600 + Crushed Time (minutes) - - a- - Intact

Figure 4 depicts the log plasma concentration-tirne protilc of crushed and intact nitëdipine PA in hrtalthy. male volunteen. This gmph clrarly shows sirnilarity in the s t o p of the dimination phases beovem the 2 different formulations. It c m dso be s m h m his p p h thiü the plasma nifrdipinr protile foIlows a one comparunent mdrl .

Individual pharrnacokinetic parameter estimates for AUCiwcllo.i2,.

AUCc,hdla.i2,, their associated log values and the mean aithmetic A ~ C c ~ h c d ~ ~ - ~ ~ ~ A U C i n t ~ C t ~ O - I I I

ratios are presented in Table 7 on page 43. Al1 ratios are greater than 100 with an arithmetic

mran value of 127.5 15.8. This result indicates that AUCcnühcd(O-12) was greater than

AUCinma(o-12) for al1 subjects.

Mean arithmetic pharmacokinetic parameter estimates for AUC(o.ir) are presented in

TABLE 6. The mean arithmetic AUC,,hed(Gi2, was 225.9 * 90.8 ng*h/ml. The mean arithmetic

AUCinmct(o.i2, was 180.1 * 76.6 ng*h,ml. The mean arithmetic area for the crushed formulation

was 25.4% greater than the mean area for the intact formulation. This is consistent with the

A~C,,h,dio-12>/AUCintPCI~~O121 ratio in Table 7.

Table 40 (Appendix H on page 1 18) and Table 4 1 (Appendix 1 on page 1 19) presents

additional pharmacokinetic data. including individual AUCo.ii data and AUCU, data. It can be

seen From Table 40 and Table 41. that the AUCinmtto-lz~ was on average 89.6% of the

AUCinwtOe, and AUCcncshrd(O-l 21 was on average 87.2% of the AUC,,hed4~e,.

The four way AVONA table for log transfomed AUCïmhur~iz~AUCinraEt~~-lI) data is

presented in Table 8 on page 43. ANOVA for AUCo-i2 reveals that the sequence. subject and

formulation variance was statisticdy different between the AUCcnishcd(~-~21 and AUCintûct,o-ir,. ail

having a p = 0.00 1.

The geometric AUC-hedlo.ir~AUCinl,t(o-iu ratio is 126.6 and the 90% CI is 120.8 - 132.7. Both of these values are outside of the 80 - 125% b o u n d q for bioequivalence. Inter-

and intra-subject varîability for AUC(O.~~, is 8.7 and 60.3%. respectively.

Raw Scale 1 Loe Scale Subject Intact Crushed Ratio Intact Crushed

AUCklZ AUCO-12 ln(_AUC0-12) ln(AUC0-1d 185.6 259.9 140.0 5.2 5.6 153.1 210.6 137.6 5 .O 5.3

TABLE 8 - FOUR WAY ANOVA COMPARING CRUSHED AND INTACT ADALAT @ PA FOR AREA UNDER THE CONCENTRATION-TIME CURVE TO TIME 12 HOURS (AUC0.12)

LN AUCPIZ SS df MS F P Sequence 0.1059 1 0.4059 52.84 0.0001 Subject(sequence) 6.9776 19 0.3672 47.8 1 0.000 1 Period 0.00 1 2 1 0.00 1 2 0.16 0.6966 Formulation 0.5832 1 0.5832 75.92 0.0001 Error 0.1 459 19 0.0076

Total 8.1138 41 Intra-subject CV = 100 x (~~~es idua l ) ' . ' = 100 x (0.0076)~.' = 8.7% Inter-subject CV = 100 x (MSS(subject) - MSWI)'' = 100 x ((0.3672-0.0076)/2)'~~ = 60J0/.

46

Figure 5 and Figure 6 depict the decrease in AUCo.i2 and AuCo, between the crushed

and the intact formulations. It is clear that there is a general trend in almost al1 subjects that the

concentration is higher in the crushed formulation than then intact Formulation for both AUCa.i2

and AuCo--

FIGURE 5 - COMPARISON OF AUCelz BETWEEN CRUSHED AND INTACT ADALAT @ PA

555

505

455

405

355 O a 305

255

205

1 55

1 O5

55 Crushed Intact

Formulation Max and Min

FIGURE 6 - COMPARISON OF AUC- BETWEEN CRUSHED AND INTACT ADALAT @ PA

1

I

1

i 405 - - 1

355 - J I 1

i I

j 1 1

55 , 1

Crushed Intact

Formulation Max and Min

TABLE 10 - FOUR WAY ANOVA COMPARINC CRUSHED AND INTACT ADALAT @ PA FOR

AREA UNDER THE CONCENTRATION-TIME CURVE TO INFINITY (Auch)

Subject

1 2 3 4 5 6 7 8 9 10 1 I 12 13 14 15 16 17 18 19 20 21

Mean SD CV

Sequeace 0.3586 1 0.3586 38.85 0.0001 Subject(sequence) 7.3942 19 0.389 1 42.1 6 0.000 1 Period 0.0023 1 0.0023 0.25 0.62 Formulation 0.4557 1 0.4557 49.36 0.0001 Error 0.1754 19 0.0092

Total 8.3863 41 Inm-subject CV = 100 x (~~~es idua l ) ' . ' = 100 x (0.0092)~,' = 9.6% Inter-subject CV = 100 x (MSS(subject) - MSU)'.~ = 100 x ((0389 1-0.0092)/3_)~.~ = 62.0%

TABLE 9 - AUCb (NC*HIML)

Raw Scale Intact

AuCo, (ng*h/rnl)

21 1.1 171.8 311.3 161.6 3 15.4 138.4 180.2 362.5 161.3 163.2

ANALYS~S DATA

Log Scale

Intact ln(AUCk)

5.4 5.1 5.7 5.1 5.8 4.9

Crushed AUCk

(ng*h/ml) 289.9 226.1 347.9 207.3 334.1 1 63.9 35 1.8 478.5 213.6 21 1.3

Crushed 1n(AUCo4)

5.7 5.4 5.9 5.3 5.8 5.1

Ratio

137 132 112 138 1 06 118 140 132 132 129 1 08 97 113 128 166 123 137 1 07 145 102 116

124.3 16.7 0.1

5.2 5.9 5.1 5.1 5.4 4.7 4.7 5.4 4.5 S. 1 4.3 5.5 5.9 5.8 5.6 5.2 O .5 0.1

21 1.3 1 12,8 108.8 228.2 90.5 157.3 73 .O 246.9 350.8 332.1 263.2 254.2 108.4 O .4

5.5 6.2 5.4 5.4 5.4 4.7 4.8 5.7 5.0 5.3 4.6 5 -6 6.2 5.8 5.7 5.5 0.4 O. 1

228.5 109.8 123.1 29 1.8 1 50.5 192.8 100.3 263.1 509.9 338.4 305.2 207.2 87.6 0.4

Individual pharmacokinetic parameter estimates for AUCinucUoai

AUCmhc<uo-P,. their associated log values and the mean arithmetic AUC,kd(o, JAUCinrxt(o-r,

ratios are presented in Table 9 on page 45. Al1 ratios are greater than 100 (except for subject 12)

with an aiithrnetic mean value of 124.3 * 16.7. demonstrating that AUCcrÿihcd(O-+l was greater

than AUC,nma(o-,, for 95% of al1 subjects.

Mcan arithmetic pharmacokinetic parameter estimates for AUC,o,l are presented in

TABLE 6. The mean aithmetic AUCcmhed(a,, was 254.2 * 108.4 ng* h/ml. The mean arithmetic

AUCin,,(o,, was 207.2 * 87.6 ng* Mml. The mean ari thmetic area for the crushed formulation

was 22.6% greater than the mean arithmetic area for the intact formulation. This is consistent

with the AUCcwhni(o-i2>/AUC,.,,(o.12~ ratio presented in Table 7. Table JO (Appendix H on page

1 18) and Table 41 (Appendix I on page 1 19) also details individual AUCo, data.

The four way AVONA table for log transfonned AUC,hedIo+jAUC,n,,1,~141 data is

presented in Table 10 on page 45. ANOVA for AuCe, reveals that the sequence. subject and

formulation varience differed significantly between the AUCcncthcd(O-t) and AUCln,l(o-xl. al1

having a p = 0.00 1.

The mean geometric AUCc~hed~04)/AUCin~C1~OOX:~ ratio is 1 23 2. This value is within the

80 to 125% b o u n d q for bioequivalence testing. However. the 90% CI for

AUC-hd~o~>/AUClntut~O-s, 1 17.0 - 129.7 extends bepnd the samr boundary. Inter- and intra-

subject variability for AUC(o,l is 9.6 and 62.0% respectively.

Mean arithmetic and geornetric pharmacokinetic parameter estimates for Cmav are

presented in Table 6. Individual Cm&&mhed. associated log Cmêu vdues and the

Cma.Lmh,&ma~i,mt ratio values are presented in Table 11 on page 48. The Cmax is the

highest concentration O bserved from the s e m concentration-time pro file for eac h sub-iec t. The

mean mithmetic range for CmaxCmhed was 17.7 to 59.1 @ml and CmayinEm ranged from 15.2 to

69.4 ng/ml. The mean arh.hmetic was 40.4 * 13 -9 @mi and mean aithmetic

C m a ~ ~ ~ ~ ~ ~ was 3 1.7 k 14.4 ndrnl. The mean arithmetic C ~ & X ~ ~ ~ ~ was greater than C m a ~ ~ ~ ~ ~

by approximately 8.8 ngml or 27.7%. These results agree with the increased AUCmhCd results

and it is logical for the crushed drug to have a greater maximum concentration with its

accompanying greater AUCçniJhcd.

The four way AVONA table for log transfonned C~&Y,~&~X+C~.,~ data is presented

in Table 12 on page 48. According to the Cmav ANOVA. sequence. subject and formulation

were significant variance factors. The rnean geometric Cm&~-~~dCmau~,,, ntio is 129.8 and

the accompanying 90% confidence interval for the C ~ ~ L X ~ ~ ~ ~ ~ ~ / C ~ ~ X ~ ~ ~ ~ ratio is 1 1 7.4- 143 S.

The 129.8 ntio falls outside the 80- 125% boundary required for bioequivalence. The intra- and

inter subject variability for Cmax is 18.8% and 53.1 % respectively.

Subiect Raw Scale 1 Log Scate - -

C r n a ~ ~ ~ ~ ~ Cmaxiatact Relative ( nglml) (ndml) Cmax (%) ~ ~ ( C ~ a & m h ~ d )

59.08 34.80 170 4.08

TABLE 12 - FOUR WAY ANOVA COMPARINC CRUSHED AND INTACT ADALAT @ PA FOR

MAXIMUM PLASMA N~FEDIPINE CONCENTRATIONS (CBIAX)

Ln Car,i.u SS df MS F P Sequence 0.6033 I 0.6033 17.02 0.0006 Subject(sequence) 5.6995 19 0.3999 8.46 0,0001 Period 0.0988 1 0.0988 2.79 0.1 115 Formulation 0.7 128 1 0.7128 20.1 1 0.0003 Error 0.6736 19 0.0354

Total 7.7879 41 1.7502

Figure 7 is a graphical cornparison of the Cmax values for each subject in the crushed and intact

formulations. In virtually dl cases. the CrnouCmId is greater than the Cmauin,,. Subject 19

(orange X ) is contrary to this trend. This subject's findings will be discussed in detail in the 6.5

Outliee section on page 60.

FIGURE 7 - COMPARISON OF CMAX BETWEEN CRUSHED AND INTACT ADALAT @ PA

O 4 1 t 1

Crushed Intact

Formulation

Figure 7 is a prdph dcpicting ihc C'mm value in ngml of al1 subjrcts with the crushed and intact formulaiions. mis grdph indicaies thrit d l crushed Cmiu v d u a an. Irirgcr than the ÿssociatcd intact C m a ~ vrilurs. cxccpt h r subjcct 19 (orange - Ks). ïhc n~ults hr subjrct 19 discuss~'d in the O U ~ I E R S scction on pagc 60.

Individual kkmhed and kaintm and associated log(ka) values are presented in Table 13 on

page 5 1. Mean arithmetic phmacokinetic parameter estimates for k h w and kainmt are

presented in TABLE 6. Absorption rates were calculated using the WinNonlin computer

program. based on computer fining of the individual concentration-time profiles to either a one

or two compartment rnodel. WinNonlin was able to converge al1 subjects to a one cornpartment

model. WinNonlin was able to fit 67% of the data to a 2 compartment model. and in al1 cases

the AiC number was smaller. determining that a 2 cornpartment model fit the data better. Ka

values used in analysis were the values with the better AIC number. Nurnbers in shaded boxes

in Table 13 are those subject's data that did not converge on a 2 compartment model. 76.2% of

the crushed data fit a 2 compartment model and 57.2% of the intact data tfit a 2 compartment

model.

Mean anthmetic values for both khnuhrd 0.0627 i 0.1374 min'' and kain,,, 0.055 1 * 0.0508 min" Adalat @ PA are very similar. K h h c d was larger than ka,,,, by 13.7% and

differed by only 0.0076 min".

The four way ANOVA for log transformed ka data is presented in Table 14 on page 5 1.

According to the ka ANOVA. sequence (p = 0.0070) and subject (p = 0.0268) were significant

variance factors. There is no statistically significant variance when comparing period or

formulation: al1 p values are > 0.05. There is no significant difference in ka between a 20 mg

dose of crushed and intact Adalat @ PA. when administered to healthy. male volunteen. The

intra- and inter subject variability for ka is 71.3% and 100.5% respectively.

-- --

Sequence 4.642212 1 4.642212 9.14 0.0070 Subject(sequence) 24.031 92 19 1.264838 2.49 0.0268 Period 0.944025 1 0.944025 1.86 0.1887 Formulation 0.724156 1 0.724156 1.43 0.2472 Error 9.651146 19 0.508

TABLE 13 - KA (MIN*') AYALYSIS DATA

Total 39.99346 41 8.083231 Intra-subiect CV = 100 x (~~~es idua l ) ' . ' = 100 x (0.5880)'.~ = 71.3%

Subject

I 2 3

Log

Ukawushed)

-2.51 4.16 -3.32

4

Raw h m h n i

min-^) 0.0815 0.01 57 0.0363

Scale

Wkainoct)

-2.38 -3.90 -3.51

Scale kaintact

0.0924 0.0202 0.0299

0.6532 0.1795 1 -0.43 5

1

0.0278 6 0.0098 7 0.0085 8 0.01 56 9 0.0081 I O 0.0621

-1.72

11 12 13 14 15 16 17 18 19 20 21

Mean SD CV

-2.58 -2.31 4.97 -3.47 -2.76 -2.3 1 -3.39 -3.25 -4.77 -3.65 -3.92 -4.41 -3.1 O -1 -70 -3.07 4.19 -3.11 -2.89 -2.99 -0.10

1

0.0758 0.0994 0.0070 0.0310 0.0631 0.0992 0.0336 0.0389 0.0085 0.0259 0.07 98 0.0122 0.0452 0.1821 0.0084 0.0493

0.0230 0.01 54 0.01 72 0.0062 0.0836 0.0582 0.0293 0.0585 0.0463 0.0151 0.0447

0.0627 0.1374

2.1 9

-3.58 -4.62 -4.76 -4.16 4.82 -2.78 -3.77 -4.17 -4.06 -5.09 -2.48 -2.84 -3.53 -2.84 -3.07 -4.19

0.0355 1 -3.1 1

0.0557 0.0504 0.91

-2.77 . -1 -98

0.78

6.4.5 C W A U C

Individual and mean arithmetic pharmacokinetic Cm&x/AUCmhed and CmadAUC,,,,

parameters values and associated log Cmax/AUC values are presented in Table 15 on page 53.

Using the highest observed concentration in a subject' s concentration-time pro file and dividing

that value by the subject's AuCo, determined the CmadAUC value.

Mean arithmetic values for Cmav following administration of the cmshed tablet

(0.17 t 0.04 h-') and intact tablet (0.16 t 0.04 h-') were very similar. While the

Cmau/AUCcmhed was larger than Cma.AUCinIm the difierence was only 0.0 I h-' or 6.3%.

These values indicate that the crushed and intact Adalat @ PA tablsts were absorbed at a sirnilar

rate when the difference in AUC is considered.

The four way ANOVA for log transformed CmadAUC data is presented in Table 16 on

page 53. There is no statistically significant difference in variance when comparing sequence.

subject, penod or formulation: al1 p values are > 0.05. Therefore it c m be concluded that there

is no statistically significant difference in Cmax/AUC between a 20 mg dose of cnished and

intact Adalat @ PA. when administered to healthy. male volunteen. The intra- and inter subject

variability for CmadAUC is 20.9% and 25.5% respectively.

I Crushed I Intact

TABLE 16 - FOUR WAY ANOVA COMPARING C M ~ L ~ / A U C ~ ~ ~ ~ ~ ~ ~ AND CMA.U/AUCp,TAn

Ln CMAVAUC ss df MS F P Sequence 0.03 16 1 0.03 16 0.72 0.4055 Subject(sequence) 1.6496 19 0.0868 1.99 0.0717 Period 0,0939 1 0.0939 2.15 0.1590 Formulation 0.0286 1 0.0286 0.66 0.4282 Error 0.8302 19 0.0436

TotaI 2.6339 41 0.2845 [nrra-subject CV = 100 x (~s~es idual)"' = 100 x (0.0.436)~.' = 20.9% Inter-subject CV = 100 r (MSS(subject) - M S R / ~ ) ' - ~ 100 x ((0.0868-0.0.0436~2)~~~ = 25.5%

Mean anthmetic pharmacokinetic parameter estimates for and Thginma are

presented in TABLE 6. Mean arithmetic and individual lag times are presented in Table 1 7 on

page 55. Lag times were calculated using the WinNodin computer program. based on computer

fitting of the individual concentration-time profiles to either a one or two compartment model.

WinNonlin was able to converge al1 subjects to a one cornpartment model. WinNonlin was able

to fit 67% of the data to a 2 compartment model. and in al1 cases the AIC nurnber was smaller.

determinina that the data fit a 2 cornpartment rnodel better. Tlag values used in analysis were

the values with the better AIC nurnber. Nurnben in shaded boxes in Table 17 are Tlag values

that did not converge on a 2 compartment model. 76.2% of the cmshed data tit a 2 compartment

mode1 and 57.2% of the intact data fit a 2 compartment model.

The mean arithmetic Thgin, was 23.1 * 12.9 minutes and was longer than the mean

arîthmetic Th&,hd at 9.5 k 8.8 minutes. Crushing the Adalat @ PA tablet decreased the lag

time by 14.5 minutes or approximately 59%.

The four way ANOVA for log transfomed lag time data is presented in Table 18 on page

54. Formulation is a statistically significant factor when comparing lag time. This indicates that

by cmshing the Adalat Q PA tablets. nifedipine was available to the body 14.5 minutes sooner

than the intact tablets.

The intra- and inter subject variability for Tlag is 1 12.8% and 130.5%. respectively.

TABLE 18 - FOUR WAY ANOVA COMPARING T L A G ~ ~ ~ ~ ~ ~ ~ AND T L A G ~ , , , FOR ADALAT @ PA

Subject

LN TLAG SS df MS F P Sequence 5.8534 1 5.8534 4.6 0.0477 Subject(sequence) 44.4668 1 9 2.3404 1.84 0.1 1 16 Period 0.62 19 I 0.6219 0.49 0.4946 Formulation 14.6688 1 14.6688 1 1.53 0.0037 Error 20.3599 16 1.2725 Total 85.9708 38 24.7569

TIa%,b& (min)

T l a g i ~ t (min) in(Tla&rushed) In(Tlagintact)

6.4.7 KE

Mean arithmetic and individual ke parameters are presented in Table 19 on page 57.

Mean pharmacokinetic parameter estimates for kemhcd and keinbd are presented in Table 6. Ke

values are detennined using the slope of the terminal phase of the individual log transformed

concentration-time profiles.

Mean arithmetic ke values for kekmhed and keinm are 0.0060 * 0.0016 min-' and 0.0054 * 0.00 15 min-'. respectively. The crushed elimination rate constant is 0.0006 min-' or 1 1.1 %

fater than keintxt. Elimination rate constants for cmshed and intact formulation are very

similar.

The four way ANOVA for log transfomed absorption rate data is presented in Table 20

on page 57. Statistical analysis suggests that only subject is statistically significant with a

p = 0.0004 when comparing kecWhed and keinm. Adalat @ PA tablets. The intn- and inter-

subject variability for ke is 18.2% and 39.2% respectively.

TABLE 19 - KE (MIN-') ANALYSE DATA

1 Raw Seale 1 Log Scale

TABLE 20 - FOUR WAY ANOVA COMPAWNG CRUSHED AND INTACT ADALAT @ PA FOR

RATE OF ELIMINATION (KE)

Sequence 0.0 124 1 0.0124 0.38 0.5474 Subject(sequence) 3.23 16 19 0.1 70 1 5-14 0.0004 Period 0.0056 1 0.0056 0.17 0.6847 Formulation O. 1205 1 0.1205 2.64 0.0716 Error 0.6288 19 0.033 1 Total 3.9990 41 0.3417

Mean arithrnetic and geometric phamacokinetic parameter estimates for Tmax are

presented in Table 6 and mean individual Tmax parameten are presented in Table 21 on page

59. The time of maximum concentration was greater in the intact formulation compared to the

crushed formulation. with mean arithrnetic values of and Tmau,,hed being 1 1 1.7 * 53.9 and 95.8 k 45.1 minutes respectively. By crushing the Adalat Q PA tablet the time to

maximum concentration was reduced by 15.9 minutes or 16.6%.

Reviewing the four way AVONA table for non-log transformed and Tmi i .~~ ,~ ,

data (presented in Table 22 on page 59). it is clear that formulation is not statistically different

when comparing Tmax (p = 0.1258). In fact. according to the Tmav ANOVA. subject was the

only significant variance factor between the time of mavimum concentration for the crushed and

intact Adalat @ PA.

The mean geometric Trna~,,~,~/Trnax~,,~ ratio is 85.9 and the accompanying 90%

confidence interval for the T m & ~ , ~ ~ ~ f l m ~ ~ ~ ratio is 70.8-1 0 1.1. The intra-subject

variability was calculated by dividing the SD by the mean. and this totaled 28.5%.

TABLE 22 - FOUR WAY ANOVA C O ~ ~ P A R I N G T M A . ~ ~ ~ ~ ~ ~ ~ AND T M A ; Y ~ , ~ ~ \ ~

Subject

T ~ x SS df MS F P Sequence 3327.758 I 3327.758 3.3 0.0853 Subject(sequence) 761 38.8 1 19 4007.306 3.97 0.007 1

Period 2 19.4286 I 319.4386 0.22 0.6464 Formulation 2589.758 1 2589.758 2.56 O. 1358 Error 19188.81 19 1009.938

Total 101462.6 41 11154.19

Tmaxcrushcd

(min) Tmaxintact

(min)

6.5 OUTLIERS

Outliers in a bioequivalence study are not solely identified by the magnitude of any

particular estimate. but instead by the relationship between the test and reference parameter in

one individual as compared to the test and reference relationship in al1 of the other individuais in

the data set.

Visual inspection of the data revealed that one subject deviatrd from the cxpected value

for the Cmax parameter. Figure 7 on page 49 is a graphical cornparison of the Cmav values for

cach subject in the crushed and intact formulations. In virtually al1 cases. the CrnauWM is

seater than the Cma~~~,. Subject 19 (orange X) is contrary to this trend. Figure 7 clearly - shows that the C m a ~ ~ ~ ~ ~ (69.4 ng/ml) for subject 1 9 is 43.6% greater than the Crnaucmhed (48.3

ng/ml). Not only is the trend for this subject in conflict with al1 the other subjects in the study.

the intact Cmm (69.4 nglml) exceeds al1 other Cmav values by approximately 12 ng/ml. This

value would appear to represent an uncharacteristic concentration that deviates tiom the

expected concentration by more than a reasonable arnount.

Figure 8 depicts the individual plasma concentration-time profiles for both crushed and

intact Adalat @ PA tablets for subject 19. The Cmax value occurs at time 180 minutes with a

value of 69.4 nglml. It is clear fiom the graph bat the plasma concentration at time 150 and 1 80

minutes are elevated and deviate tiom the expected plasma concentration-time profile. This

indicates that these concentration are unexpectedly large. The green circles (e) with solid line

indicate a plasma concentration-time profile without the two elevated concentrations.

FIGURE 8 - CONCENTRATION-TIME PROFILE FOR SUBJECT 19

Time (minutes) - - l- - intact A Altered Intact

Figure 8 is the individual plrisma concentration-timc protile for subjcct 19. The Cmav valut. occurs rit time 180 minutes with ti vduc of 69.4 ngml. It is clcar t'rom the p p h thaf the plasma concentrations üt timc 150 md 1 fi0 minutes arc clevated and do not drviatr from a "normal- plasma conçentntion-protilc.. Tht. grcm circles (*) with solid line indiçate a plasma conccntmtion- time protilc without the two &vatcd concentrations.

The majority of concentrations from the intact concentration-time profile for subject 19

appear to Follow the trend of the cxpected concentration-time Cumes. except For the

concentrations at 150 and 180 minutes.

6.5.1 EFFECTS OF SUWCTS 19% DATA ON A U C K E K A

By comparing the parameters of subject 19 to the observed mean for al1 subjects in the

study. it is possible to estimate the efFects of the potential outliers on the data set. The

AUCCmhCd(O-ml (509.9 ng*h/ml) for subject 19 is approximately 45% larger than the AUCinl,t(04i

(350.8 ng*h/ml). The A U C - ~ ~ ( O ~ ~ for subject 19 is approximately 100% greater thon the

mean arithmetic AUCenished(b) (254.2 t 108.4 ng*h/rnl). #en considering the large SD. and

large inter-subject varïability (62.0%) associated with AUCo,, as wel1 as the area incurred by

the increase of the 2 spurious data points. it is reasonable to assume that the AUC values for

subject 19 are within average study limits. Table 23 on page 62 lists the pharmacokinetic

parameten Cmau. mean arithmetic Cmau. Tmax. AUCci2. AuCo, and mean AUC values with

and without the possible outliee.

TABLE 23 - COMP.ARISON OF PHARMACOKINETIC PARAMETERS WITH AND WITHOUT POSSIBLE OUT LIER^

As mentioned above. CmlKinm is 43.6% greater than CmauCmhcd. Tma. values are not

Al1 points Included 2 Points Removed

From subject 19

significantly different or distinctive from the rest of the data.

Keinim (0.0065 min") appears to be almost double that of the kecmShcd (0.0035 min").

(ng/m')

69.42

However. it is unlikely that rate of elimination is the cause for the increased concentration as the

terminal phase of both curves are similar.

Mean Anthmetic Cmsx ine/mi,

31.7114.4

30.3i11.8

Table 24 details the pharmacokinetic data derived from linear and nonlinear regession

and cornputer fitting for subject 19.

Tmax (min)

180

238

TABLE 24 - PHARMACOMNETIC DATA FOR SUBJECT f 9

1 Cmshed 1 Intact

AUCosi2 (ng*h/ml)

312.6

299.7

Tlae îrnini 1 10.3 1 27.3

Tmau (min)

k8 tmin"~

AuCo, (ng*hlml)

350.8

349.2

131 0.0463

Mean Anthmetic

AuCo_,., (ngL himl)

180.6k76.6

179.5k75.5

180 0.0084

Mean Anthmetic

AuCod tngk himij

207.2k87.6

307.1287.5

Dixon's Test and the T Procedure for outliers were used to determine if the concentration

at 180 minutes (69.4 &ml) for subject 19 vas a statistical outlier. Fint. both tests were used to

compare magnitude of the Cmax value for subject 1 9 compmd to the C m m values of al1 other

subjects. Both tests were also completed on the relative ratio of Cm~,h,J/Cm~i,wt to

determine if there was a difference in the relative ratio produced for the elevated levels. Both

statistical tests determined that the serurn concentration of nifedipine at time 180 minutes for

subject 19 is not an outlier.

TABLE 25 - RESULTS OF OUTLIER TESTS FOR SUBJECT 19

1 Dixon's Test (r) [ T Procedure (T,,) 1 ResuIt Cmax 1 0.0395 1 2.620 1 Not Outlier

Cmaxcrushed/Cmaxintact Relative Ratio

Subject 19 had normal baseline characteristics. Subject 19 is a 3 1 year old male. of

height 183 cm, and weight 95.5 kg. BP at the time of physical was 156/72 mm Hg standing and

1 12/78 mm Hg while supine. HR at time the time of physical was 64 BPM. There was a 9 day

washout penod between subject 19's study days.

0.1232 1 1 I

Criteria for Outlier 1 r > 0.450 Tn > 2.733 1 -

There are severd possible sources for this deviation including: analysis error. lab error.

dose error. Iabeling error. or vioiating the protocol.

64

The difference observed at 150 and 180 minutes could suggest analytical lab error. In

most cases of error of this type. the sample would be reanalyzed. However. no reanalysis was

completed due to limited accessibility to laboratory equipment.

It is unlikely that subject 19 received more than the prescribed 30 mg dose during his

intact phase of the study. Dose was administered by the principle investigator and easily

controlled. However. it is possible that the subject received less than 20 mg during the cmshed

phase of the study. This could occur by incomplete consumption if the drug from the mortar.

This did not occur as al1 apparatus involved was inspected by the principle investigator. and no

dmg remained following dosing. However. if during the crushed phase. the subject did receive

less than 20 mg. it would be possible to estimate the CrnaxcWhed concentration for a 20 mg dose.

Since the mean anthmetic CmauCwhed concentration was 8.76 ngmi greater than the intact.

simply adding this concentration to the intact value would estimate the CmaumhCd for subject

19. This would mean that the C m a b h e d value for subject 19 would be greater than 78 ng/ml.

While this is a possible conclusion. it is highiy unlikely. A review of the literature (Table 2 on

page 13) reveals that serum concentrations of a 20 mg dose of prolonged action nifedipine do

not reach concentrations above 70 np/rnl. In fact. al1 of the Cmm values (not including subject

19) in this study are below 60 @ml and the highest value found in the literature was

61.4 * 21.9 ng/rnl?

Therefore it is likely that 20 mg was administered during both phases of the study.

Labeling error can be considered a possible source of error. tt is unlikely that either the

principle investigator or the lab technician labeled the serum sample wrong as al1 samples were

accounted for and derived separately. Since subject participated in the study alone on both

study days. it is impossible that subject 19's s e m samples were mixed with: (i) other

participants sarnples or (ii) serum sarnples from subjects 19's other study day. Fwther still. if

the sample was analyzed correctly but mislabeled. the increased concentration would simply be

that of another t h e in the same study day. This would still be this subject 19's Cma~~.,, value.

As previously mentioned. the value of the sarnple was much higher than any found in the study

and litenture. Therefore. it is unlikely that the sample was mislabeled.

6.5.3.4 VIOLA TING THE PROTOCOL

hother possibility is that the subject violated the protocol. This could alter the results of

the speci fic study day without effecting the other phase of the study. For example. if the subject

decided to dnnk grapef'it juice on the morning of the intact phase. This would increase the

arnount of nifedipine in the systemic circulation for that study day. It is impossible to detemine

if the subject broke protocol in any way. but when questioned specifically about grapehit juice.

the subject denies having consumed any.

Based on this evaluation. while the concentrations at 150 and 180 minutes following the

intact tablet in subject 19 appear to be larger than expected. there is no apparent reason to

explain the unexpected values, and. in fact, the concentrations were not observed to be outliers

staristically. Therefore. while the most obvious reason for error would be andytical error. these

concentrations were left in the data set and analysis canied out without exclusion of any points.

The mean pharmacodynamie parameter estirnates for SBP. DBP. HR and MAP are listed

TABLE 26 - MEAN PHARMACODYNAMIC PARAMETERS SBP, DBP, HR, MAP

Individual maximum. minimum and change in SBP and DBP values for both crushed and

intact formulations are presented in Table 42 and Table 43 (APPENDIX J and APPEND~X K on

Reference Formulation (Intact)

page 130 and 1 3 1 ) respectively. TABLE 27 presents the mean maximum. minimum and change

Test Formulation (Crus hed)

in SBP and DBP values.

Time . (min)

0

Time (min)

0

TABLE 27- MEAN MAXIMUM, MINIMUM AND DIFFERENCE IN SBP AND DBP DATA

HR (BPM) 67.1

MAP (mm Hg)

93.1

SBP (mm Hg)

121.6

SBP (mm Hg)

123.9

DBP (mm HE)

77.6

DBP (mm Hg) 76.0

1 CV(%) 1 10.8 1 8.6 1 5 3 2 1 15.9 1 12.7 1 59.8 1

MIN DBP (mm Hg) 67.6 9.0 133 67.7 8.6

MAX DBP (mm Hg)

78.4 11.0 14.0 76.8 12.2

HR (BPW 67.8

ADBP (mm Hg)

10.8 I

5.9 I

54.9 9.1 5 -4

MAP (mm Hg) 9 1.2

MINSBP (mm Hg)

i 10.8 9.5 8.6

1 12.0 9.7

M A X SBP (mm Hg)

124.8 f 2.0 9.6

133.3 13.3

Intact

Crushed

ASBP (mm Hg)

14.0 6.4

45.8 11.3 6.0

Mean SD

CV (%) Mean SD

6.6.1 BLOOD PRESSURE REDUCTION

6.6.1. i SYSTOLK BLOOD PRESSURE

Mean SBP values are presented in Table 26 for each sampling time. Figure 9 is a graph

of the BP vs. time. It is important to note that the y-auis is limited in range to more clearly show

the data. The results fiom both Table 26 and Figure 9 demonstrate a reduction in SBP from

time zero to approximately 240 minutes.

Crushed and intact values show a similar reduction in SBP between time O and 200

minutes. Average SBPinmCt decreased by 14.0 6.4 mm Hg (1 24.8- 1 10.8 mm Hg). as presented

in Table 27 on page 66. The SBPmid of the Adalat @ PA tablet reduced by 1 1.3 * 6.0 mm Hg

(123.3-1 12.0 mm Hg). Therefore the intact tablet was able to reduce SBP 2.7 mm Hg greater

than the crushed Adalat d PA tablet. This value is clinically unimportant.

FIGURE 9 - LMEAN SYSTOLIC BLOOD PRESSURE READ~NCS OF CRUSHED AND INTACT ADALAT

& Crushed Tirne (minutes) - - l- - Intact

Figure 9 is the m m SBP r a d i n e for both crushed and intact tomulations. The= is an obvious darmsr in SBP of appronirnately 10 mm Hg during the fimt Zûû minutes of the ~ ~ d y day in both formulations. SBP p d u d l y i n c m r s t'ollowinp 100 minutes as the effects of the nifedipine wear off. Note that the y-a.is has been altered to bener depict the dam

uitra- and inter-subject variability are 4.6% and 3 3.6% respectively.

Review of the tive way ANOVA table for SBP (Table 28 on page 68). reveais that that

variables: sequence. subject, period and time are statistically significant with respect to the

difference in BP readings. Formulation is the only parameter that does not statistically affect the

difference in systolic BP readings.

TABLE 28 - FIVE WAY ANOVA COMPARING SBP RECORDINGS FOR CRUSHED AND INTACT ADALAT @ PA

Sequence 0.0465 1 0.0465 21.82 0.0001 Su bject(sequence) 3.1 650 19 0.1 139 53.44 0.0001 Period 0.0429 1 0.0429 20.1 1 0,0001 Formulation 0.0007 1 0.0007 0.35 0.557 Time 0.3852 99 0.0039 1.82 0.0001 Error 0.6994 328 0.0021

Total 3.3398 4 9 452.3398 Intra-subject CV = 100 x (~~~esidual)~ ' = 100 n (0.002 1 )O = 4.6% Inter-subject CV = 100 x (MSS(subject) - M S W ~ ) ~ ' = 100 x ((0.1 139-0.001 1 VI)" = 33.6%

Figure I O is a graph of SBPcnishd and SBPiniaa of all subjects. Each subject's maximum

and minimum SBPcmhed was compared to the corresponding rni~virnurn and minimum SBPintnn.

FIGURE 10 - ~MA,YII).SUM AND MINIMUM SBPlmJtn AND SBPcRuSHED

Cnished Crushed Intact SB? Intact SBP SBP Max SEP Min Max Min

Formulation Max and Min

Figure 10 prcsents the rnrtvimurn and minimum SBP reading of both cmhed and intact nifedipinc: formulations. AI1 subjects' decrrrisc: in BP over tirne and similarity o f the slops o f dl lines indicrite that BP d u c t i o n is similm in dl subjects. Note that tfic y-axis hm b e n altrred to bettrr rrprexnt the data

6.6.1.2 DIASTOLK BLOOD PRESSURE

M e a . maximum. minimum and change in DBP values are presented in Table 26 on page

66 for each time of s e m collection. Figure 1 1 is a graph of DBP vs. time. It is important to

note that the y-ais is limited in range to more clearly show the data. The results from both

Table 26 and Figure 11 demonstrate a reduction in DBP from time zero to approximately 340

minutes.

Crushed and intact values show a similar reduction in DBP between time O and 200

minutes. Mean DBP,",, decreased 10.8 * 5.9 mm Hg (78.4 - 67.6 mm Hg) as presented in

Table 27 on page 66. The crushed formulation of the Adalat @ PA tablet reduced DBP 9.1 * 5.4

mm Hg (76.8 - 67.7 mm Hg). Therefore the intact tablet was able to reduce DBP 1.7 mm Hg

p a t e r than the crushed Adalat @ PA tablet. This value is clinically unimportant.

FIGURE 11 - MEAN DBP READINGS OF CRUSHED AND INTACT ADALAT @ PA T.ABLETS

O 200 400 600 + Crushed Time (minutes)

- - l - - Intact

Figure 1 I is the m m DBP mdings for both crushed and intact formulations. Thrre is an obvious dec~asc. in DBP o f appmximatefy 8 mm Hg dun'np the first 300 minutes of the study day in both fomulations. DBP gndually incmsts tbllowing JO0 minutes as the etTects of the nifedipine w w ofE Note h a t the y-mis hris b e n dtered to bener depict the diitii.

Intra- and inter-subject CV values are 6.6% and 43.8% respectively.

The five way ANOVA for DBP (Table 29 on page 70) demonstrates that the sequence

and subject are the only factors that are a significantly source of variance with respect to the

reduction in DBP. Formulation. period and time are not statistically significant with regards to

the difference in diastolic BP.

TABLE 29 - FIVE WAY ANOVA COMPARING DBP RECORûlNCS FOR CRUSHED AND INTACT ADALAT @ PA

Sequence 0.43 54 1 0.4354 100.06 0.000 1 Subject(sequence) 3.688 1 19 O. 1941 6 1 0.0001 Period ~.0!45 ! 0.0 1 46 - 5 .- CI.0679 Formulation O .O024 1 0.0024 0.55 0.4573 Time 0.4888 99 0.0049 1.13 0.2073 Error 1.4371 328 0.0043

Total 6.0564 449 455.0564 Inm-subject CV = 100 x ( ~ ~ ~ e s i d u a l ) ' ' = 100 x (0.00~3)'~ = 6.6% Inter-subject CV = 100 x (MSS(subject) - M S R / ~ ) ' ~ = 100 x ((0.194 1 -0 .0~3 ) / 2 )~ ' = 43.8?h

Figure 12 is a graph of the DBP for al1 subjects separated into test and reference product.

Each subject's maximum and minimum DBPcnahed was compared to the corresponding

maximum and minimum DBPinuct.

Crushed Crushed Intact DBP lntact DBP DBP Max DBPMin Max Min

Formulation Max and Min

Figure 13 reprrsents the mavimum and minimum DBP readings of both crushed and intact nikdipine hmulations. All subjects' dereaw in DBP over tirne and similarity of the slopes ofafl lines indicate that DBP reduction is sirnilx in al1 subjects. Note that the ymis has b e n dtered to better represent the data,

The mean HR measurements for each sample time are presented in Table 76 on page 66.

Figure 13 on page 7 1 illustrates a graph of the mean HR produced tiom subjects administered

crushed and intact Adalat GO PA tablet over the 12 hours study day. The results From both Table

26 and Figure 13 demonstrate that HR does not significantly tluctuate throughout the course of

the study. There is a large and clinically insignificant jump in HR at tirne 360 minutes. which

c m be explained by study day procedure.

FIGURE 13 - MEAN HEART RATE READINCS OF CRUSHED AND INTACT ADALAT @ PA TABLETS

O 200 400 600 -+- Crushed Time (minutes) - 4 - - Intact

Figure 13 is a p p h of the m m CIR in BPM of al1 subjects for both crushed and intact ni kdipine PA tiiblrts. HR does not clinicrilly or statistically alter during the tlrst 240 minutes of the study da?. A signitlcant incxase in HR at timr 360 minutes was anributed to the movement and intakc of food following the 240 samplr time. Fi& and HRi- do not clinically or statistically alter form cach other,

Intra-subject and inter-subject CV values are 6.7% and 5 1.4% respectively.

Table 30 on page 72 is the five way N O V A cornparhg the HR for intact and crushed

Adalat @ PA tablets. Statistically significant parameters include sequence. subjects and time

(p = 0.000 1). Non-significant parameters include penod and formulation.

TABLE 30 - FIVE WAY ANOVA COMPARING HEART RATE MEASUREMENTS FOR CRUSHED

AND INTACT ADALAT @ PA --

SS df MS F P Sequence 0.47 2 6 1 0.47 16 102.67 0.000 1 Subject(sequence) 5.0647 19 0.2665 58.03 0.0001 Period 0.003 1 0.0034 0.75 0.3875 Formulation 0.0052 1 0.0052 1.14 0.287 Time 0.8789 99 0,0088 1.93 0.0001 Error 1.5067 328 0.0045

6.6.3 MAP

Table 3 1 on page 73 represents the values for maximum, minimum and change in MAP.

Figure 14 on page 74 is a graph of the mean MAP over tirne for crushed and intact Addat (30 PA

tablets.

. 1 - I

. - .-

Crushed 1 SD 1 10.8 9 .O 1 6.2

Intact

The results from both Table 3 1 and Figure 14 demonstnte a reduction in DBP from time

zero to approxirnately 240 minutes. Maximum and minimum MAPcnührd was 93.5 * 10.8 and

83.0 * 8.7 mm Hg. respectively. Maximum and minimum MAPimxl was 92.2 1 1.6 83.0 * 9.0

mm Hg. respectively. MAPcmhCd was reduced by 10.5 mm Hg. MAPintxl was reduced by 9.2

mm Hg. Therefore. the cmshed tabiets was able to reduce MAP by 1.3 mm Hg greater then the

intact formulation. This value is clinically unimportant.

SD CV ( O h )

Mean

8.7 10.5 83 .O

11.6 12.6 93.5

5.2 56.8 1 O S

F~CURE 14 - MEAN MAP READ~NGS OF CRUSHED AND INTACT ADALAT @ PA TABLETS

l

O 200 400 600 Crushed

Time (minutes) - - l - - Intact

Figure 14 is the m t m hlAP mdings for both crushcd m d intact formuliitions. ficn. is rrn obvious Jccrcrcie in MAP o f ripproximatcly 4-8 mm Hg during thc tint 300 minutcs of the study da? in bcith hmulations. b1AP griduaily incrtzut~ following 300 minutcs as the rtkcts of the nitkdipinr w t r t otX Notc that thc y u i s ha bcsn altsrcd to bsttsr Jcpict the data. Frinnulation doty; not clinicrilly or statistically atftxt MAP. with rc"jpect to crushed and intact nikdipint. PA.

Intra- and inter-subject CV values are 5.1% and 37.6% respectively.

Table 32 on page 74 is the five way ANOVA comparing the LlAP for intact and cmshed

.4dalat 03 PA tablets. Statistically signi ficant parameters include sequrnce. period and subjects

(p < 0.00 17). Formulation and time are non-significant piinmeters.

SS d/ MS F P

Sequence 0.21 19 1 0.21 19 80.1 0.0001 Subject(sequence) 3.7 13 1 19 0.1428 54 0.0001 Period 0.0265 1 0.0265 10 0.0017 FormuIation 0.00 14 1 0.0014 0.55 0.4605 Time 0.3 156 99 0.0032 1.2 0.1161 Error 0.8678 328 0.0026

TotaI 4.1362 4 9 453.1363 Intra-subject CV = 100 x ( ~ ~ ~ e s i d u a l ) ' . " IO0 x (0.0026)~.' = 5.1% Inter-subject CV = 100 x (MSS(subject) - MSR/~)' = 100 x ((O. I 418-0.0016)/2)~~~ = 37.6%

The intn-subject and inter-subject variability was calculated using equations 7 and 8.

Important to note is the intra-subject CV for AUCo.ir, AuCo, and Cmax; 8.7.9.6 and 18.8%.

respectively. These values are well below the intra-subject CV criteria (30%) set out during

sample size calculations.

TABLE 33 - IIYTRA- AND INTER-SUSJECT VARIABILITY FOR PARAMETER ESTIMATES AUCe, CMAX, ICA, TLAG, KE, Tmx, SBP, DBP, HR AND MAP

Parameter

AuCo-12 AuCo,, Cmax ka

Cma,dAUC Tlag

ke Tmax SBP

Based on a sample study size of 2 1 subjects with the calculated CV(%) detailed in Table

Inter- subject CV(%)

Intra- subject CV(%)

--

DBP HR

MAP

33. a = 0.05 and P = 0.8, a post hoc analysis of the detectable difference using t-values for the

Post Hoc Intra-

Subject (CVOh)

8.7 9.6 18.8 31.5 30.9 1 12.8 18.2 32.0 4.6

sample size was completed. Results of the post hoc analysis are detailed in Table 33. With an

6.6 6.7 5.1

intra-subject CV of 8.7 and 9.6%. a difference in the magnitude of 6.5 and 7.2%. respectively

60.3 62.0 53.1 1 13.8 25.5 130.5 39.2 55.6 33.6

for AUCci2 and AuCo, couid be detected. Also. with an intra-subject CV of 18.8% for Cmax.

6.5 7.2 14.0 23.5 15.6 79.8 13.6 33.8 3 ,4

43.8 5 1.3 37.6

a difference in the magnitude of 14% could be detected. important to note are the values for

4.9 5 .O 3.8

76

SBP. DBP. HR and MAP. With intra-subject differences of 4.6.6.6,6.7 and 5.1% respectively.

a difference in the magnitude of 3.4.4.9. 5.0 and 3.8% couid be detected.

Table 34 on page 76 is a summary of the AUCa, and Cmav ratio and the 90% CI for

TABLE 34 - SUMMARY OF VARIABLES REQUIRED FOR BIOEQUIVALENCE

This study does not suggest bioequivalence between crushed and intact nifedipine PA

tablets with respect to the pharmacokinetic parameters rate and extent of absorption. in healthy.

AuCo-12 AUC- Cmav

male volunteers. according to the guidelines from Health Canada.

90% CI 120.8 - 132.7 1 17.0 - 129.7

d a

Crushedfintact Ratio 126.6 123.2 129.8

ResuIt Failed Failed Failed

7.0 Drscussro~ This study has demonstrated that cnishing Adalat @ PA, while it does not effect rate of

absorption absorption (ka and CmadAUC), does reduce Tlag and increase the extent of

absorption (AUC). However. in nomals, the increase in nifedipine concentrations was not

associated with a sipificant change in BP and there were no precipitous falls in BP.

7.1 PHARMACOKINETICS

nie debate conceming the safety of SL nifedipine has been ongoing. The medical

literature is filled with pharmacokinetic and pharmacodpamic snidies and case reports detailing

the drawbacks or benefits of thenpy deaiing with acute hypertensive emergencies or urgencies.

OHen. the kinetics of the administration of nifedipine is at the root of these debates. This study

was desiped to examine the pharmacokinetics and pharmacodynarnics of Adalat @ PA. crushed

and intact. in hralthy volunteers in order to determine if the crushed nifedipine tablet will retain

a similar pharmacokinetic and pharmacodynamic profile. Ultimatel y. the investigators of this

study wish to replace the use of SL nifedipine with cmshed Adalat @ PA tablets in situations

where possible.

7.1.1 EXTENT

Analysis shows that the cnished Adalat Q PA tablet had a higher bioavailability than the

intact Adalat GO PA tablet. 22.7% more of the dmg was available when the dmg was crushed.

We were able to accurately detect more than 80% of the concentration-tirne profile with the 15

plasma samples in 12 houn. This is shown by the AUCmhed(~-i2>IAUCahtd(OirI (87.2%) ratio

and the AUChmclio. i2{AUCin,loc, (89.6%) ratio.

ANOVA indicates that the variance for formulation. sequence and subject were

statistically significant (p = 0.0001) between the AUC of the crushed and intact tablets. The

penod effect was not significant (p = 0.06200).

However. when calculating the least significant difference (e.g. sequence - 8.6%) that can

be detected by the parameters in ANOVA. it is apparent that very srnaII. clinically unimportant.

differences are capable of being detected.

There were no positive baseline concentrations observed in this study indicating that

there was an adequate washout period and hence any significant period effect is a statistical

outcome likely created by the low intra-subject variability observed with this and most othrr

parameters. The significance of sequence and subject cm also be attributed to the inter- and

intra-subject variability. and it is believed that formulation is responsible for the 27.7%

difference in AUC. Inter-subject variability is 9.6%. which is well below the specified 30%

estimate used in the study design.

According to the HBP criteria for bioequivalence. cnished Adalat (€0 PA fails to meet the

specified conditions for extent of absorption with that of intact Adaiat @ PA. The geometric

AuCo, test io reference ratio is within the 80425% boundary (123.2), yet the 90% CI (1 17.0-

129.7) fails to meet this criteria.

The HPB0s criterion for comparing the rate of absorption is to employ Cmau as the

primary metnc. There is an inherent problem with the application of this cntenon. Cmêu is not

a pure measure of dmg absorption. but is affected by extent. When extent is equal. Cmax is

more reasonable estimate of comparative rate, but does not measure the rate of absorption

directiy. K a however. is a direct measure of the rate of absorption. A computer-generaied

estirnate of ka was used as a direct measure of rate of absorption in this study. CmadAUC has

aiso been considered an effective metric to measure rate because it is independent of rxtent of

absorption. In order to fully audy and compare the rate of absorption. this analysis will

examine k a Cmax and Cma'dAUC.

Since AUCcmshcd was larger than AUCin,,-. it follows that C r n a ~ , , ~ ~ ~ would also be

larger. CmaxCmhd (40.4 * 13.9 ng/ml) was approximately 27.7% higher than Cmrtu,,,, (3 1.7

k14.4 ngml).

ANOVA analysis indicates that the variance for 3 facotrs. namely. formulation. seqliencc

and subject are statistically significant (p < 0.0006) when comparing Cm&yahed and Cmau,,,,.

The argument made for AUC also applies for Cmau. Significant subjcct differences can be

cxplained by the inter-subject variability. LSD evaluation for sequence provides evidencr that

small clinically unimportant differences are capable of being detected by the sequence

parameter. Formulation. however, is a significant parameter when evaluating Cmau.

[ntra-subject variability for Cmax is 18.8%. This value is still well within the 30%

cntena implemented earlier.

Statistical analysis indicates that the Cmax measure fails to meet the HPB criterion for

bioequivalence. The geometric CmaxardCmaxhmt ratio (129.8) fdls outside of the 80- 125%

80

boundary. Therefore. according to Cmaw, the rate of absorption is different enough for the

crushed and intact formulations of nifedipine to be bio-inequivaient.

The primary goal ofthis study was to determine if cmshing the Adalat @ PA tablet

would result in a safe. graduai and sustained pharmacokinetic and pharmacodpamic profile.

By proving that the crushed Adalat 0 PA tablet will 'act' the same as the intact tablet is

hdanièntal io the outsonir of tliis studk. One uT ille impurtant priniaq ouicornes of Lhis study

was to provide data regarding the sustained and graduai profile of the absorption of both cnishrd

and intact nifedipine. A direct cornparison of the rate of absorption would establish the safety

profile of the crushed tablet compared to the intact tablet. Since the AUCs between crushed and

intact are statistically different, it is more accurate to use ka or CmadAUC as a measure of rate.

WinNonIin was able to fit al1 subject data to a one or two cornpartment mode1 and

determine absorption rate constants for al1 subjects. The ka;mshed was 0.0627 * 0.1 374 min-' and

kainmLT was 0.055 1 * 0.0508 min-'. These values are very similar with less than 17% difference

between them. Crna?dAUCcUhcd was 0.1 7 k 0.04 h" and Crnau/AUC,,L, was 0.16 + 0.04 h-1.

These values differ by only 6.3%

None of the parameters analyzed in the ANOVA for ka or CmadAUC are statistically

significant. Important to note is that formulation was not statistically different. Therefore.

crushing the nifedipine PA tablet. does not significantly alter the rate of absorption of Adaiat @

PA as compared to the intact tablet.

This analysis is contrary to the results of the Cmax analysis which would suggest that

there is a statisticai difference between the absorption of both crushed and intact Adalat @ PA

tablets.

Post-hoc andysis detemines that even with the large 3 1.5% inter-subject variability for

ka this study was able to detect a 22.3% difference. if such a difference exists. This value is

8 1

still below the 25% criteria allowed at the begiming of our study. Also, post-hoc analysis

detemines that the 20.9% inter-subject variability for CmadAUC. the study able to detect a

15.6% direrence, if such a difference exists. This value is still below the 25% criteria alfowed

at the beginning of our study.

The measure of the rate of absorption sometimes depends on the Tmav and Tlag. Since

the crushed nifedipine PA tablet is aiready disintegrated when it enters the GI tract. it is

available for absorption faster than the intact formulation. Intact tablets must tint fiagrnent and

break before a substantial arnount of the drug is available for absorption. It would be expected

that by crushing the Adalat @ PA tablet prior to dosing. we can significantly reduce the lag-time

that accompanies the disintegration phase of most drugs. This was observed with our data.

Crushing the PA tablet reduces the hg-time on average by 14 minutes (TIâgdiffmncl) or 59%.

fiom 23 to 9 min. based on the best fit of a one cornpartment mode1 calculated by WinNonlin.

However. the time of maximum concentration for Cmax,,h,d (95.8 45.1 min) was

faster than the Tmainmt (1 1 1.7 53.9 min) by approximately 15.9 minutes (Tmau~ji~,,) or

14.2%. The difference in Tma~~~~,,,,, and Tla&iiRmnc, is oniy 2.9 minutes. Therefore. the

'arnount' of time that the intact dmg was absorbed was only 2.9 minutes longer than the crushed

tablet.

The crushed formulation was absorbed sooner and correspondingly it reached the

maximum concentration sooner. The opposite is tnie for the intact formulation. Tlaginm was

longer and Cma~~, , was achieved later.

hdyz ing the ANOVA table for Tlag indicates that formulation is a statistically

significant (p = 0.025 1). Therefore we cm conclude that formulation alone is responsible for

82

the differences in lag time. This is expected. As mentioned above, crushing the tablet will

eliminate the disintegration phase and dnig absorption will commence faster.

ANOVA for Tmax indicates that subjects are the only statisticaily significant variable

(p = 0.0021). Again this is expected due to the large inter-subject variability that accompanies

the absorption of a cimg.

Similar in importance to absorption is elimination. The elimination profile of intact

Adalat 0 PA is well known. There is ody an 1 1.1% difference in the elimination time of the 2

formulations. with the intact tablet eliminating faster.

ANOVA indicates that there in no statistical difference in elimination rate constant with

respect to formulation. ANOVA supports that only subject differences are statistically

significant (p = 0.0004). Therefore. crushing an Adalat @ PA tablet dors not statistically effect

the elimination of the dmg fom the body.

With an inter-subject variability of 18.3% we notice that we are able to detect a

difference in the magnitude of 12.9%. This value is within the critena established before the

study.

7.2 PHARMACODYNAMICS

7.2.1 BLOOD PRESSURE

BP was reduced by approximately 10 to 12 mm Hg in al1 subjects \ with both cn shed and

intact Adalat 09 PA tablet. A reduction of 10 to 12 mm Hg is significant enough to alter

subject's classification of BP (Table 1 on page 4)

Table 44 (Appendix L on page 122) lists the pharmacodynamie parameters grouped by

phase. It is clear that there is no significant difference in mean SBP at time t = O brtween phase

1 (124.6 13.1 mm Hg) and phase 2 (121.0 * 13.1 mm Hg).

7.2.1.2 SYSTOLIC BP REDUCTION

Mean SBPcnrrhçd and SBPintm decreased by 14.0 * 6.4 and 1 1.3 * 6.0 mmHg respectively.

The di fference between SBPemhed reduction and SBPinwa reduction. 2.7 mmHg. is not cl inicall y

si gni ficant.

With a p = 0.557. formulation is not a statistically significant whrn comparing cnished

and intact SBP reductions, in other words. the crushed nifedipine reduces SBP to a similar

degree that intact nifedipine does.

Time is a direct variable that is manipulated when using a BP reducinp agent. The goal

of therapy is to reduce the BP over time. As the BP reduces over time the variable becornes

statistically significant. Therefore, it is expected that time would be a statistically significant

variable.

84

Inter-subject variation accounts for the differences observed with the subject parametee

in ANOVA. As al1 people will respond to nifedipine to a different degree. it is expected that the

subject variable would produce statistically significant results.

Phase and penod were also statistically significant. This was not expected. In a 7-way

cross-over bioequivalence study. significant period effects imply cross over (e.g. positive drug

concentration at iime z m in phase 2). Positive concentrations were not o b s m - d at tinic t = O

in phase Z.and so pharmacologie carryover is unlikely. It is more likely that SBP values were

more elrvated during phase 1 than phase 2. because subjects were uncasy and anxious by the

snidy procedures and the venous catheter in phase 1. Since no positive concentrations were

observed in this study. the protocol employed an adequate washout period. The significant

period effect is a statistical outcome likely created by the low intn-subject variability observed

with this and most other parameters.

A cornparison c m be made between the phase 1 and phase 2 reduction in SBP (Table 45

in Appendix M on page 123). While the results of ANOVA suggest a significant difierence in

sequence. Table 45 indicates that there is only a 3.6 mm Hg difference in SBP. Even though the

difference is si p i ficant. the magnitude of the difference is smalI(< 4 mm Hg) and this is

generaily regarded as clinicaily not unimportant.

Figure 15 on page 85 is a graph of the mean SBP versus the mean concentration of

nifedipine. The SBP deceases as the concentration of nifedipine increases. Linear regression of

the concentration-effect data for SBP concludes that the slopes are not statistically different

(p = 0.1 734). The similarity in the slopes of the lines demonstrates that the crushed and the

intact formulation of nifedipine reduce the SBP to a similar degree with equivalrnt increases in

nifedipine concentration.

Figure 15 is a p p h of the mLm SBP vs. mLm concentration of nikdipinr.. As thr conccntntion ot'nikdipinr incrits thc SBP cfscnwes. Solid ruid dont4 linrs rcprt?;cnt thc l i n m corrcliition of the SBP rtriuction and the incnmt. in concentmtion. Slopcrj ot'thc cnrshrd (-0.2074) and intact (-0.2587) data arc stritistidly insigniticant (p = 0,1734). Note ihat the y w i s hu bccn limitsd to bctter dcpiçt the data

Table 44 (Appendix L on page 122) lists the phmacodynarnic parameters grouped by

phase. It is clear that there is no significant difference in mean DBP at time t = O between phase

1 (77.0 k12.4 mm Hg) and phase 2 (76.6 1 1.5 mm Hg).

Mean DBP,,hcd and DBPin,,,, decreased by 9.1 k 5.4 and 10.8 i 5.9 mm Hg respectively.

The di fference between DBPCmhrd and DBPinmt, 1 -7 m d g . is not cl inical ly signi ficant.

Therefore the intact nifedipine formulation did not clinically lower the DBP significantly more

than the crushed nifedipine formulation.

Similar to the SBP variables. formulation is not statisticaily significant. p = 0.4573.

Therefore. formulation is not a statisticdly different variable when cornparhg DBPmkd and

DBPinmL In other words. the crushed nifedipine reduces DBP to similar degree that intact

nifedipine does.

86

Inter-subject variation accounts for the differences observed with the subject parameten

in ANOVA. As al1 people will respond to nifedipine to a different degree. it is expected that the

subject variable would produce statistically significant results.

Sequence was also statisticdly significant. This was not expected. A cornparison can be

made between the phase 1 and phase 2 reduction in DBP (Table 15 in Appendix M on page

!2?). Mile the results of ANOV.4 silggest a significant differe~ce in sequence. Table 45

indicates that there is only a 0.7 mm Hg difference in DBP. Even though the difference is

si gni Bcant. the magnitude of the di fference is srnaIl(< I mm Hg) and this is generally regarded

as clinically unimportant.

Figure 16 on page 87 is a g a p h of the mean DBP versus the mean concentration of

nifedipine. The DBP deceases as the concentration of nifedipine increases. Linear regession of

the concentration-effect data for DBP concludes that the slopes are not statistically different

(p = 0.7562). The similarity in the slopes of the lines demonstrates that the crushed and the

intact formulation of nifedipine reduce the DBP to a sirnilar degree with equivalent increases in

nifedipine concentration.

FIGURE 16 - MEAN DBP VS MEAN CONCENTRATION OF NIFEDIPINE

Concentration (nglml) + Cntshed I Intact - Linear (Crushed)

O - Linear (Intact)

Figurc 16 is a gmph of the mrm DBP VS mem concentration oTnifL.dipinr. .As thc concsntrition ofnikdipine incrcasrs. thr DBP dernflsrs. Solid and ciotted lines wpresent the lintrr comlrition orthe DBP rcduction and the i n ç ~ u e in concrntntion. Slopcri of the crushed (-0.0682) and intact (-0.0850) datri âtr: nntistkdly insignit?cani (p = 0.7562). Note thüt ihr: y-mis hiis bwn limited to bcner depict the data

Administration of nifedipine is commonly associated with reflex tachycardia caused fiom

the need for increased coronary perfusion fiom the enlarged arterial diameter. In fact. the

results of this study show the opposite effect. As the concentration of ni fedipine increases. the

average HR decreases. Figure 17 on page 89 clearly shows the effects of increasing nifedipine

concentration on the HR. This study was done in normal healthy males. Results rnay be

different if subjects were hypertensive patients. Healthy volunteers are able to maintain stable

HR under rninor arterial vasodilation. Cardiac output is a tùnction of HR and stroke volume

(CO = HR x SV). A healthy heart is easily able to increase its SV to increase CO whilr

maintaining a constant HR. The subjects in this study were al1 healthy volunteen. as judged by

a physician. Subjects were able to maintain the samr HR by altering their SV to counter the

tachycardic effects of nifedipine.

Sympathetic stimulation is able to increase the contractility of the heart. The FRANK-

STARLING LAW OF THE HEART States that the heart purnps d l b100d retumed to it. With artenal

vasodilation. the hrart must be able to pump more blood through larger arteries. Under

sympathetic stimulation. a healthy heart can compensate for a sustained increase in afterload by

edarging (through hypertrophy of the cardiac muscle fibes)68. Hypertensive patients or

patients with stenosis. the ventricle must generate more pressure. In hypertensive patients. the

increased pressure and increased stroke volume dong with dmg induced dilation of the arteries

results in an increased HR to maintain CO.

ANOVA indicates that formulation is not a statistically significant parameter regarding

HR. Inter-subject variation accounts for the differences observed with the subject parameters in

ANOVA. As ail people will respond to nifedipine to a different degree. it is expected that the

subject variable would produce statistically significant results.

Phase was also statistically significant. This was not expected. A cornparison can be

made between the phase 1 and phase 2 reduction in HR (Table 45 in Appendix M on page 123).

While the results of ANOVA suggest a significant difference in sequence. Table 45 indicates

that there is only a 0.3 BPM difference in HR. Even though the difference is significant. the

magnitude of the difference is small (< 1 BPM) and this is generally regarded as clinically

Figure 17 on page 89 is a graph of the mean HR versus the mean concentration of

nifedipine. The HR deceases very slightly as the concentration of nifedipine increases. This

reduction in HR of approximately 3 BMP is clinically unimportant. Linear regression of the

concentration-etTect data for HR concludes that the dopes are not statistically different

(p = 0.7603). The simiiarity in the dopes of the lines demonstrates that the crushed and the

intact formulation of nifedipine reduce the DBP to a similar degree with equivalent increases in

nifedipine concentration.

y = -0.0986~ + 71 .O04 Co"centmthl (nglml) + Crushed

y = -0.0683~ + 69.547 I intact " - Linear (Intact) - Linear (Cnished)

Fisure 17 is ri p p h of the m m HR V S mem concentration of nifedipine. As the concenmtion of nifidipine incmscs. there is a slight d e m m e in HR A closer look rcveais thrit the HR only demases by itpproximatcly 4 BPM with a 30 @ml inmase in concentration. Solid and dotted lines q m e n t the lin= correlation of the HR and the i n c m in concentration. Slopes ofthe crushed (-0.0.986) and intact (-0.0.683) datri are statistidly insignificant (p = 0.7603)- Note thcit the y-axis has been limited to bettrr depict the data

7.2.3 M A P

Table 44 (Appendix L on page 122) Iists the pharmacodynarnic parameters grouped by

phase. It is clear that there is no significant difference in mean MAP at time t = O between

phase 1 (92.9 i 1 1.9 mm Hg) and phase 2 (91.4 * L 1.6 mm Hg).

MMmid and Win, decreased by 9.2 *5.2 and 10.5 * 6.2 mmHg respectively.

bïAPinm was abie to reàuce MAP by I .3 mm& more than MMcrushcd. This difierence in

reduction is not clinically signiticant.

The most important variable of the ANOVA is the formulation. W ith a p = 0.46 1.

formulation is not a statistically different variable when cornparine MAPcmrd and MAP,,,, In

other words. the cmhed nifedipine reduces MAP to the sarne degree that intact nifedipine does.

Inter-subject variation accounts for the differences observed with the subject parameten

in ANOVA. As al1 people will respond to nifedipine to a different degree. it is expected that the

subject variable would produce statistically significant results.

Phase and penod were also statistically significant. AS mentioned in the discussion of

SBP positive concentrations were not observed at time t = O in phase ?.and so pharmacologie

carryover is unlikely. it is more likely that MAP values were more elevated during phase I than

phase 2. because were uneasy and anxious by the study procedures and the venous catheter.

A cornparison c m be made between the phase 1 and phase 2 reduction in SBP (Table 43

in Appendix M on page 123). While the results of ANOVA suggest a significant difference in

sequence, Table 45 indicates that there is O difference between mean MAPphaei (9.9 5.8) and

mean MMphnrel (9.9 I 5.7).

Figure 18 on page 9 1 is a graph of the mean MAP versus the mean concentration of

nifedipine. The MAP deceases as the concentration of nifedipine increases. Linear regression

of the concentmtion-efTect data for MAP concludes that the slopes are not statistically diferent

(p = 0.5005). The similarity in the dopes of the lines demonstrates that the crushed and the

intact formulation of nifedipine reduce the MAP to a similar degree with equivalent increases in

nifedipine concentration.

FIGURE 18 - MAP VS CONCENTRATION OF NIFEDIPINE

Y = -0.1 1 2 9 ~ + 90.g4q Concentraion (nglml) ~rusheâ

y = -0.1427~ + 90.482 lntact - Linear (Crushed) - - Linear (Intact)

Fiputt 18 i s ri p p h of the m r r n MAP VS m a n conccntntion ot'nifcdipinc. As the conccntntion of ni fidipine incrcascs. the MAP dcçrcascs. Sulid and dottcd linrkj wpwsent the Iintur comlation of the MAP rcduçtion and Ihc incnusc in conccntntion. Slopes of the crushed (-O. 1 129) and intact (-0.1427) datri are stritisticrill~ insignitïcant (p = 0.0.5005). Note that the y-mis has b m limiteci to bt'ttt'r dtpict the Jnm

Previous studies have described the pharmacokinetic and pharmacodynamic profile of

intact Nfedipine. This study was designed to compare the pharmacokinetic and

pharmacodynamic profile of a crushed Adaiat 0 PA tablet to the well studied intact Adalat @

PA tablet.

This study provides clinical data to suggest that crushed Adalat 4D PA tablets provide a

gradua1 and sustained reduction in BP similar to that of the intact formulation. Unfortunately. C

ihis study failed to prove that crushed and intact Adalat 43 PA tablets produce bioequivalent

p harmacokinetic characteristics. Rate and extent of absorption failed to meet the cnteria

required by the HBP to adequately prove bioequivaience.

The pharmacokinetic profile of crushed Adalat @ PA tablets failed to meet the criteria

with respect to rate and extent ofabsorption to be considered bioequivalent with the intact

tablet. The AUCcmhed was 22.7% higher than the AUC,nD,. This significant increase in extent

of absorption resulted in an AUCcmhd/AUChmC, ratio of 123.2 and a CI of 1 17.0-129.7. which

falls outside the 80- 115% boundary required by the HPB guidelines. Furthemore. CrnauLmhed

concentrations were 8.8 ng/ml higher then C ~ Z K ~ ~ ~ concentrations. The C m a ~ ~ ~ ~ / C m a ~ ~ ~ ~ ~ t

ratio was 129.8: well outside the 80- 1 25% boundary required by the HPB guidelines.

However. this snidy did provide important clinical data to support the hypothesis that

nifedipine PA tablets will produce a sirnilar gradual and sustained BP reduction when crushed.

Previous midies have demonstrated that that intact nifedipine PA tablets decreased BP in

nomal. healthy volunteen and in hypertensive patients. Similar ka and CrnaidAUC values

produced in this study, indicate that the rate of absorption of both crushed and intact nifedipine

PA tablets are similar. The crushed Addat Q PA was able to produce a safe. gradud and

sustained but statistically significant reduction in SBP, DBP and MAP without elevating HR.

93

Recognizing that cmshing a formulation of a drug cm alter its absorption. distribution.

metabolism and elirnination. one can speculate that the pharmacokinetic results of our study

may be attributed to an increased bioavailability produced when cmshing the Adalat 0 PA

tablet.

This study was designed to determine the similarities and differences of crushed and

intact Adalrit 2 P A tablets. hlthough thc findings failcd to provc phaiiacokinctic

bioequivalence. the data demonstrates that the pharmacodynamic safety profile of crushed

nifedipine PA tablets is similar to that of intact tablets.

Further studies are warranted to:

1) Study the et'fects of crushed Adalat 43 PA tablets in hypertensive patients. It is important

to detennine if there will be a significant difference in BP reduction From this study in

hypertensive patients. Whilc: this study was able to demonstrate that the BP reduction

achieved by both crushed and intact tablets was similar. it cannot provide data regarding

the effects of cnished Adalat @ PA in hypertensive patients. A study to determine if the

increased bioavailability of the crushed tablet would differ significantly in hypertensive

patients appears warranted.

2) This study was able to verify that the safety profile of nifedipine remains after crushing.

Investigaton should conduct a controlled study in acute asymptomatic hypertensive

patients with an NG tube. A snidy of this sort would provide concrete data to either

support or reject the efficacy of crushed nifedipine PA tablets in acute asymptomatic

hypertensive patients.

REFERENCES

Gifford R. Management of hypertensive crises. JAMA 199 1 ; 266:829-235.

Dean SK. MJ;. Nifedipine in the treatment of difficult hypertension. European Journal of

Clinical Pharmacology 1983; 24: 1-5.

Grossman EM. FH: Grodzicki. T: Kowey, P. Should a moratorium be placed on

sublingual nifedipine capsules given for hypertensive emergencies and

pseudoemergencies? JAMA 1996; 276: 1328- 133 1.

Schwartz MN. JE: Yeshurun, D.: Sharf. B:. Oral nifedipine in the treatment of

hypertensive urgency: cerebrovascular accident foilowing a single dose. Archives of

Internal Medicine 1990: 150:686-687.

Wachter R. Symptomatic hypotension induced by nifedipine in the acute treatment of

severe hypertension. Archives of Internal Medicine 1987: 147556-558.

Zangerle KW. R. Syncope and conduction disturbances following sublingual nifedipine

for hypertension. Annals of Emergency Medicine 1985: 14: 1005- 1006.

OIMailia JS. GE: Giles. TD. Nifedipine-associated myocardial ischemia or infarction in

the treatment of hypertensive urgencies. Annals of Intemal Medicine 1987: 107: 185- 1 86.

Van Harten JB. K; Danhof. et al. Negligible sublingual absorption of nifedipine. Lancet

1987: 1363.

McAllister R. Kinetics and dynamics of nifedipine afier oral and sublingual doses. The

Amencan Journal of Medicine 1986; 8 12-5.

Al-Waili NHN. Efficacy of sublingual veraparnil in patients with severe essential

hypertension: compaxison with sublingual nifedipine. Eur Journal Med Res 1 999: 4: 193-

198.

95

Angeli PC. M; Caregaro. L; Merkel, C: Sacerdoti. d; Rondana M: Gatta A. Cornparison

of sublingual captopril and nikdipine n imrnediate treatment of hypertensive

emergencies. A randomized. single-blind clinical trial. Archives of Intemal Medicine

1991: 15 1 :678-682.

Diker EE. S. 1s sublingual nifedipine administration superior to oral administration in the

actite treatment of hypertension? Angidogy ! 092; 43:47748 1.

Messerli FK. P: Grodzicki. T. Concem over inappropriate use of sublingual nifedipine

(Letter). Inpharma 199 1 : Oct 26.

Messerli FK. P Grodzicki. T. Sublingual nifedipine for hypertensive emcrgencies. Lancet

1991: 338:881.

Messerli FG. E. The use of sublingual nifedipine: a continuing concem. Archives of

Interna1 Medicine 1999: I59:SX9-60.

Opie L. Sublingual Ni fedipine (Letter). The Lancet 1 99 1 : 338: 1 203.

Gonzalea-Cmona VI-P. C: Je des-Sanchez. C. Single dose sublingual nifedipine as the

only treatment in hypertensive urgencies and emergencies. Aniology 199 1 : 42908-9 13.

Kobayashi EK. Y: Fujimura. A. A potential risk of sublingual nifedipine treatment in

surgically treated patients in Japan. Cntical Care Med 1998; 26: 12%.

Ides CJ. OC; Milnes. FJ. Sustained release nifedipine and atenolol as initial treatment in

blacks and maiignant hypertension. British Journal of Clinical Pharmacology 1986:

21 :377-383.

Joint National Cornmittee on Detection E. And Treatment of Hi& Blood Pressure. The

sixth report of the Joint National Cornmittee on Detection. Evaluation and Tre~tment of

High Blood Pressure. Bethesda: National Institutes of Heaith, 1997:Reprinted from the

Archives of Internai Medicine November 24. Vol 1 57, 1 997. pages24 13-24.16.

96

Kaplan N. Clinical Hypertension. Baltimore: Williams & Wilkins, lW8:.1.W.

Massicotte AM. WM. Hypertension. Canadian Pharmaceutical Journal 1987; 120:706-

716.

Kowalski JM. Report - Cardiovascular Institute of the South. 1999.

Canada H. Hypertension. http://wv.hc-sc.gc.ca/hppb/ahi/hypertensiodindex.html2000

- May.

Perloff DG. C: Flack. J: et al. Human blood pressure determination by

sphygmomanornetry. Office of Scientific A f i n . Arnencan Heart Association 1993:

88 :2460-2470.

Gillis M. Compendium of Pharmaceuticals and Specialties. Adalat PA. Vol. 34th:

Canadian Phannacists Association. 19992052.

www.dmgtopics.com/brand.himl. June 1 1 th. 2000.

Lichtlen PR. A. Adalat: A comprehensive review. Germany: Springer-Verlag. 199 1.

Banzet OC. SN: Thibomier. M; Singlas, E: Alexandre. M; Corvol. P. Acute

antihypertensive e ffect and pharmacokinetics of a tablet preparation of ni fedipine.

European Journal of Clinicai Pharmacology 1983: 24: 145- 1 50.

Kleinbloesem CVB. P: Van Linde. JA: Voogd. PJ: Breimer. DD. Nifedipine: kinetics and

dyamics in healthy subjects. Clinical Pharmacology & Therapeutics 1984; 35742-739.

Ueno KK. S: Uemoto. K: Ikada T. Effects of food on nifedipine sustained release

preparation. Annals of Pharmacotherapy 1989; 23 :662-665.

Ramsch K. Zur pharmakokinetik von nefedipin. Scherpunkt Medizin 198 1 : 455-6 1.

Kleinbloesem CVB. P; Van Harten. J: Danhof. M; Breimer. D;. Nifedipine: influence of

rend function on pharmacokinetics/hemodynmaic relationship. Clinical Pharmacology

and Therapeutics 1985; 37563-574.

97

Murdoch DB. N. Sustained release nifedipine formulations. Drugs 199 1 ; 4 1 :73 7-779.

Foster TH. SR; Richards, VR: Bryant. PJ. Graves. DA et al. Nifedipine kinetics and

bioavailability afier single intravenous and oral doses in normal subjects. Journal of

Clinical Pharmacology 1983; 23: 16 1- 170.

Klienbloesem CVB. P; Faber. H; Danhof. M; et al. Variability in nifedipine

pharmacokinetics and iiy namics: a ncw osidaiion poly morphisni in nian. Bi~slirniiçül

Pharmacology 1984: 33:372 1-3724.

Hoyo-Vadillo CC-H. G: Herrera. JE: Vidal-Gante. J; Moreno-Ramos. A; Chavez. F;

H0ng.E. Pharrnacokinetics of nifedipine slow release tablet in Mexican subjects: further

evidence for an oxidation polymorphism. Journal of CIinical Pharmacology 1989:

29:8 16-820.

Bailey DMA. J.M.O.: Srong, H: Spence. J. EtTects of grapefruit juice and naringin on

nisoldipine pharmacokinetics. Clinical Pharmacology & Thenpeutics 1993: 54589-594.

Neuvonen PK. T: Kivisto. K. Simvastatin but not pravistatin is very suscaptable to

interaction with the CYP3A4 inhibitor itraconazole. Clinical Pharmacology &

Therapeutics 1998: 63:332-34 1.

Josefesson MZ. A.L.; Ahlner. J. Effect of grapefniit juice on die pharmacokinetics of

amlodipine in healthy volunteers. European Journal of Clinicd Pharmacology 1 996:

51:189-193.

Bailey DS. D: Munoz, C ; Arnold. J. Interaction of citnis juices with felodipine and

nifedipine. Lancet 199 1 ; 337:268-269.

Pisarik P. Blood pressure-lowering effect of adding grapehit juice to nifedipine and

terazosin in a patient with severe renovascular hypertension. Archives of Family

Medicine 1996; 5:4 13-426.

98

Guengerich Fm. M; Beaune, P; Krernen. P: Wolff. T: Wamann. D. Characterization of

rat and human liver microsornai cytochrome P-450 forms involved in nihdipine

oxidation. a prototype for genetic polymorphism in oxidative dnig metabolism. The

Journal of Biological Chemistry 1986; 26 1 505 1-5060.

Bailey DMA. J.M.O.: Srong. H; Spence. J. Grapehit juice and naringin interaction with

nitrcndipine [abstract]. Clinical Pharmacology B Therapeutics 1992; 5 1 : 156.

Soons PV. B: Rossemalen. M: Schoemaker. H: Uchida E: Edgar. B: Lundahl. J: Cohen.

A: Breimer. D. Grapehit juice and cimetidine inhibit stereoselective metabolism of

nitrendipine in humans. Clinical Pharmacology & Therapeutics 199 1 : 50:394403.

Fuhr UM. A: Blume. H: Muck. W: Unger. S: Staib. H. Gnpemiit juice increases oral

nimodipim bioavailability [abstract]. European Journal of Clinical Pharxnacology 1994:

47:A 100.

Yee GS. D: Pessa L: Della Costa T: Beltz S; Ruiz. J: Lowenthal. D. Effect of grapefruit

juice on blood cyclosponn concentration. Lancet 1995: 345955956.

Garg SK. N. Bhargava V: Prabhakar. S. Effect of ppefnti t juice on carbarnazepine

bioavailability in patients with epilepsy. Clinical Pharmacology & Therapeutics 1998:

64:286-288.

Kantola TK. K: Neuvonen. P. Grapefniit juice greatly increases serum concentrations of

lovastatin and lovastatin acid. Clinical Pharmacology & Therapeutics 1 998; 63 :3 97-40 1.

Lilja K. K: Backrnan. J: Lamberg, T; Neuvonen. P. Grapefniit juice substantiaily

increases plasma concentrations of buspirone. Clinical Pharmacology & Therapeutics

1998: 64:655-660.

99

Debbas NJ. SH: Shah, K; Abrams, SM, Johnston. A: Turner, P. The bioavailability and

pbannacokinetics of slow release nifedipine during chronic dosing in volunteers. British

Journal of Clinical Pharmacology 1986: 2 1 :385-388.

Armstrong JC. VF: Macklin. BS; Renwick. AG; Waller. DG. The influence of two types

of meai on the pharmacokinetics of a modified-release formulation of nifedipine (Addat

Retard). E uïopcan Journal of Clinicai Phaiaîology 1997: 53: 1-1 1 - 1-13.

Elliott HM. PA. Clinical pharmacokinetics of nifedipine. Implications for the care of the

elderl y. Drugs and Aging 1997: 1 1 :470-479.

Lobo JJ. DB: Kendall MJ. The intra- and inter-subject variability of nifedipine

pharmacokinetics in young volunteers. European Journal of Clinical Pharmacology 1986:

3057-60.

Pabst GL. D: Moles. H: Dahrnen. W: Jaeger. H. Pharmacokinetics and Bioavailabiliy of

three ditTerent nifedipine preparations. deim-Forsch / Dmg Research 1986: 36257-

259.

Hoyo-Vadillo CC-H. G: Herrera. JE; Vidal-Garate. J; Salazar. LA: Moreno-Rarnos. A:

Chavez. F: Tena. 1; Hong,E. Pharmacokinetics of oral nifedipine: relevance if the

distribution phase. Journal of Clinical Pharmacology 1989: 29:X 1-256.

Shaheen OZ. S: Qussuois. Y; Arafat. T; Mouti. H. Pharmacokinetics and

pharrnacodynamics of two commercial oral ni fedi pine products. International journal of

Clinical Pharmacology. Therapy & Toxicology 199 1 ; 29:337-34 1.

Kristen RN. K; b t e n D: Heintz, B. Clinicd pharmacokinetics of vasodilators Part 1

(Review). Clinical Pharmacokinetics 1 998; 34:457-482.

Henry PD. Amencan Journal of Cardiology 1980: 46: 104%

100

Khan AL. SJ; Mullins. FG: Dixon. JS. Toon. S. The phannacokinetics and

pharmacodynamies of nifedipine at steady state during concomitant administration of

cimetidine of high dose ranitidine. British Journal of Clinical Pharmacology 199 1 ;

32:s 19-522.

Lubowski TIN. C.H: Sweeney, K; Quinitani. R. The relative bioavailability of

ternafloxitcin adminiaterd ihruugh a nasagas&ric tube with iind hithout eiiteral feédiiiy.

Clinical Pharmacokinetics 1993: 2243-47.

Vincent JT. R: Pelletier. S; Willavize. S; Friedman. H. The bioavailability of nasogastric

venus tablet-form or oral trovatloxacin in healthy subjects. The Amencan Journal of

Surgery 1998: 176:23~-26s.

M m o AB. L.P. Bioequivalence. Arzneim.-Fonch/Drug Research 1995: 45: 1 09- 1 1 5.

HPB. Conduct and Analysis of Bioavailability and Bioequivalence Studies: Part A.

Ottawa: Heaith and Wel tàre Canada, 1 992: 1 -80.

Rarnsch KG. K: Scherling. D: Sommer. J: Ziegler. R. Pharmacokinetics and Metabolism

of Calcium-Blocking Agents Nifedipine. Nitrendipine. and Nimodipinr. American

Journal Of Nephrology 1986: 6:73-80.

Stolley D SB. Sample size caiculations for clinical pharmacology studies. Clinical

Pharmacology & Therapeutics 1 986; 39A89-490.

Deletti EH. Steinijans. VW. Sample size determination for bioequivalence assessrnent by

mean of confidence intervals. International Journal of Clinical Pharmacology. Therapy

and Toxicology 199 1 : 29: 1-8.

Shenvood L. Human Physiology: From Cells to Systems. New York: West Publishing.

1993.

APPENDIX A - ANTIHYPERTENSIVE AGENTS FOR ACUTE HYPERTENSIVE EMERGENCIES

TABLE 35- ANTIHYPERTENSIVE AGESTS FOR ACUTE HYPERTENSIVE E~~IERGENCIES"

/ Sodium nitroprusside (iv

Diuretics:

Direct Vascular smooth muscle relauants:

Chlorothiazide (iv. po) Furosemide (iv. po) Diazoxide (iv)

Aipha Adreneryic Recepior Blockers :

Adrenol ytic Agents:

Beta-Adrenergic Receptor Blocken:

'Siredipine capsules not includcd nor indicatcd. iv, intravcnously: im, intrsmuscularly: po. onilty.

Hydralazine (iv. im. po) Kitroglycerine ( iv j Dibenzylene (iv) Phenoxybenzamine ( po) Methyldopa (iv. po) Reserpine (im. sub-q. po Trimethaphan camsy late Cryptenamine (iv) Propranolol (iv. PO) Esmolol (iv)

AlphdBeta Adrenergic Receptor Blocken: AC E inhibitors: Calcium antagonists:

Dopamine Agonist

Labetalol (iv. po) Lisinopril (iv. PO) Diltiazem (iv. po) Vrnparnil (iv. po) Nicardipine (iv. po) Fanoldaparn (iv)

INFORMED CONSENT FORM

Pharmacokinetics and Pharmacodynarnics of intact and Crushed Nifedipine Prolonged Action Tablets (Adalat PA@) in

Healthy, Male Volunteers

You are volunteenng to participate in the study described below. Once you have a reasonable understanding of the study and a11 your questions have been satistactori l y answered. you will be asked to sign below to indicate your free consent to participate in the study.

You are being asked to volunteer for a study involving the use of nifedipine. a medication used to control blood pressure and chest pain. The purpose of this study is to examine the effects of nifedipine (i.e. blood pressure) in healthy adults.

THE STUDY WlLL BE CONDUCTED AS FOLLOWS:

1. There are two parts to the study. Each phase is 12 hours long separated by a minimum 73 hour (3 day) wash-out period. During each study phase. you will receive either an intact or a crushed nifedipine prolonged action tablet.

2. There are three study days. The first will occur at the beginning of the study to obtain baseline data. The other two study days will occur at the end of each study phase.

3. You will be asked to abstain from alcoholic beverages. grapemiit juice. and caffeine- containing foods such as coffee. tea chocolate. and colas for 48 hour (2 days) pnor to and throughout the study day.

4. On the study days. you will be asked to be present at the designated study unit at 7:00 a.m. Blood sample, and blood pressure measurement will occur at 730 a.m. You will be asked to take yourmoming dose of Nifedipine at 8:00 a.m.

5 . A catheter (needle) will be inserted into a vein in your forearm for the purpose of blood sampling. Afier the catheter is in place. you should not expenence any additionai discornfort when the blood samples are taken.

6. Blood samples will be taken at 0,0.25.0.5.0.75. 1 .O. 1 -33. 1.67.2.0.2.j.3 .O. 4.0.6.0, 8.0, 10.0, and 12.0 hours &er the 8:00 am. 20mg dose. The catheter will remain inserted until after the 12 hour blood sample.

7. Food will be allowed four hours d e r dnig administration on the study day.

8. These procedures (steps 3-7) will be repeated on a separate study day at a pre-specified date.

A totd of 15 blood samples ( 10 m) each will be taken during each dosing regimen.

You will be asked to immediately report any side-effects that you may notice.

The study will require a complete past rnedical history and a series of laboratory tests pnor to ihc study.

The main adverse effects commonly associated with nikdipine include flushing. headache. ièeling of warmth. diuiness. or lightheadedness. al1 of which are not life-threatening.

Before agreeing to participate in this study. you should understand that:

You c m withdraw from the study at any time. You can be asked to withdnw from the study at any time iF you are Found to be noncornpliant with the study protocol. This study will be of no direct medical benefit to you. You will receive $200.00 upon completing this study. The investigator will answer any questions you have before and during the study. The principle investigator of the study. Dr. Paul Oh. c m be reached at (4 16) 480- 6760. All persona1 information obtained during the study will be held in strict confidence and p u r name will not appear in any publication or presentations that result from this work.

Consent: Your signature below indicates that you have read and understood the inComation provided and have decided to participate in the research protocol.

Patient Signature Witness Signature

Investigator Signature Date

APPENDIX C - IDEAL BODY WEIGHT BASED ON HEIGHT AND FRAME SIZE

TABLE 36 - IDEAL BODY WEIGHT BASED ON HEICHT AND F R I ~ I E SIZE

Height (cm)

155 157.5

Weight (kg) Small Frarne 58-60.8

Medium Frame 59.5-64.1

Large Frame 62.7-68 .S

58.9-61.4 1 60.5-65 63.6-69.5

APPENDIX D - NOR~MAL LABORATORY TEST RANGES FOR SUNNYBROOK & WOMEN'S COLLECE HEALTH SCIENCE CENTER

TABLE 37 - NORMAL LABORATORY TEST RANGES FOR SUNNYBROOK & WOMEN'S COLLECE HEALTH SCIENCE CENTER

Sodium 1 135-147 1 mrnoüL

Calcium 1 2.20-2.60

Potassium 1 3.5-5.0

Phosahate 1 0.8-1.5

Chloride CO2 Total

96-1 08 22-30

ALT I <40

RENAL PROFILE Urea 3.0-7.0 Creatinine 4- 1 06

-.

AST 1 < 3 7

Albumin 1 35-50

Glucose (Random) 4.0-8.0 CBC

dL

RBC Count 1 4.5-6.00 Hemo lobin 135- 170 Hematocrit 0.400-0.500

80-100 MCH 27-32 MCHC 320-360 RDW 1 10.0-14.5 Platelet Count 1 150-400 1 xlO~9/L Mean Platelet Count 1 5.0-1 5.0 1

I

Lymphocytes 1 1 .O40 1 x ~ O E ~ / L Monocytes 1 0-1.0 ( x l 0 ~ 9 f L

APPENDIX E - CASE RECORD FOW

Patient's Name:

Nifedipine Study

Case Record Form

P H A R M A C O ~ T I C S AND P ~ C O D Y N A M I C S OF

INTACT AND CRUSHED NIFEDIPINE PROLONGED ACTION TABLETS (ADALAT PAR) mi HEALTHY

MALE VOLUNTEERS

Sunnybrook & Women's College Health Science Centre Department of Pharmacy Quality Control - KI3333 2075 Bayview Avenue NORTA YORK, ONTARIO Canada M4N 3M5

Tel: (416) 480-45 10 Fax: (416) 480-4281

Date:

Patient In formation & Medical

2 ) Patient Name:

Patient Address:

Telephone Number: (Home):

(Business):

Date of Birth (dd/mrn/yy): Ag e :

Race:

3) Past Medical History

4) Does the patient have a history of any significant gastrointestinal disorders. including hepatic disease or impaired rend function?

Yes O (speci& beiow) No Q Details:

5 ) Social History:

1 Does the Subject: / Y ~ ~ o r / Consumption:

6 ) Medication History and Concomitant Medications

Smoke? Drink?

b

D W Dosage Indication Duration of Ongoing? 'ïherap y

I

cigarettes per LI day O week drinks per O day O week

7) 1s the subject known or suspected to be allergic to any medications?

Was the patient a previous smoker? O (if so how long ago)

Yes O (specrfy below) No Cl (cunriniie to question 8)

Heart Rate

Dmg Name

Standing

9) ECG Results Heart Rate: GOOD Cl

1

I

S ymptoms (attach separate note if necessary)

10) Physical Examination

Date of Iast reaction

1 System 1 Normal 1 Abnormal 1 Comrnents 1

1 HEENT 1 Cardiovascular Pulmonary Gastrointestind Neurological Musculoskeletal Geni tourinary Skin

1 1 ) Haematology and Biochemistry Results (transcribe results and attuch duplicate of laboratory report)

Laboratory Data:

S e m Electrolytes Na': (135-147) mrnoIfL K' : (3.5-5.0) rnrnoUL C 1': (96- 108) ~ n m ~ l / L HC03-: (23-30) mrnol/L POL: (0.8- 1.5) rnmol/L

(0.7-1.1) MG? ~ ~ O V L CA": (2.20-2.60) mmoK

S e m Glucose: (4.0-8.0)

Liver fùnction Tests AST: ( e 7 ) IU/L ALT: (<40) IU/L

Renal Function Tests SCR: (44-106) umoVL BIM: (3.0-7.0) mm0K

CBC & Differential

GOOD O

Comments:

INCLUSION CHECKLIST

110

YES NO

The subject is male. between 21-50 years of age The subject has been judged healthy by a medical history, by a complete physical exam and by blood haematology and biochemistry tests being within the normdreference ranges in use at Sunnybrook and Women's College Health Science Centre.

Siped informed consent has been given by the subject prior to the commencement of study procedure and following receipt of verbal and writtèn information about tliè stuJy.

The subject has a known or suspected hypersensitivity to Nifedipine.

The subject has a history of significant gastrointestinal disorders.

The subject has abnormal pre-treatment haematology or clinical biochemistry results.

The subject has used a medication known to intenct with nifedipine or any other calcium charnel blocken during the 30 days prior to enrolment into the study or is expected to require such medication during the study penod.

The subject is expected to require the use of a systemic antimicrobial agent during the course of the study.

The subject is known or suspected to be unable to comply with a study protocol or medication schedule.

(EVCL L'DE)

Q Q / EYCL L'D Ei

k i t Two & Three Date:

Patient Group:

Nifedipine Dose: Dose: 20 mg

Adverse Events:

Nature: Crushed CI Intact Q

'mis form should be used to document the adverse evmts rcpontd or obxrved during this visit Al1 scrious and uncupeçrcd mena musc k reponed to the projar monitor immediattly (WC protocol ter dctïnitions).

Adverse Event Description (Pleuse use standard medicul trrminologvl

Time of Onset of Time of Adverse Event Resolution (if

Relationship to study Dnig I = unlikety 2 = possible 3 = ~robûblv

Concomitant Medications: List below on!v those medications which huve changed since the iast visit.

Medication Dosage Date of Change Reason

4) Pharrnacokinetic Data:

BLOOD COLLECTION SCHEDULE

Subject narne:

Subject number:

Study Date:

Study Phase:

BLOOD PRESSURE MEASUREMENT RECORD FORM

Subject name:

Subject nurnber:

Study Date:

Study Phase:

STUDY TIME (hr)

PLANNED TIME

ACTUAL TIME

SYSTOLW DIASTOLIC

MAP HEART RATE

114

Cortclusioa Form

To be compieted when subject is completing/withdrawing fiom the study.

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Arnozrnf

I I I ' V S b b " i o m o e o o

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APPENDIX H - INDIVIDUAL PHARMACOKINETIC PAUMETERS FOR INTACT FORMULATION

TABLE 40 - INDIVIDUAL PHARMACOKINETIC P A ~ M E T E R S FOR INTACT FORMULATION

ka (min-') Subject

Tlag (min)

1 185.6 211.1 87.9 / 34.79 63 0.005102 2 153.1 171.8 89.1 26.32 80 0.0053 17 3 271.7 311.3 87.3 41 .O5 254 0.005099 4 144.9 161.6 89.6 1 40.26 58 0.006663 5 286.3 3 15.4 90.8 56.98 83 0.00612 6 1 19.5 138.4 86.3 30.82 151 0.005805 7 168.3 180.2 93.4 28.22 156 0.006651 8 319.6 362.5 88.2 48.35 102 0.00499 9 153.1 161.3 94.9 37.19 46 0.00847

AUCei2 ( n g * ~ m l )

AuCa, (ng*~rni )

AUC ~ ~ t i ~ (%)

Cmax (min)

Tmax (min)

ke (min")

APPENDIX I - INDIVIDUAL P H A R M A C O ~ E T I C PALWVETERS FOR CRUSHED FORMULATION

TABLE 41 - INDIVIDUAL PHARMACOKINETIC PARAMETERS FOR CRUSHED FO~IULATION

ka 1 Tlag (min") (min) Subject

1

AUCk (na* h/rnl)

289+9

AUCki2 (Rg*h/ml)

25 9.9

AUC Ratio

(%)

89.6

Cmav (min,

59.08

Tmax (min)

83

APPENDIX J - MAXIMUM, MINIMUM AND CHANGE IN PHARMACODYN~IC PARAMETERS FOR INTACT ADALAT @ PA

TABLE 12 - MAXIMUM, MINII\.IU~+I AND CHANGE IN PHARMACODYNMIIC PARAMETERS FOR INTACT ADALAT @ PA

MAX SBP 1 MIN SBP [ ASBP MAXDBP 1 MIN DBP A DBP (mm Hg)

8 .O

Subject

APPENDIX K - MAXIMUM, MINIMUM AND CHANGE IN PHARMACODYNAMIC PARAMETERS FOR CRUSHED ADALAT 03 PA

TABLE 43 - MAXIMUM, MINIMUM AND CHANGE IN PHARMACODYNAMIC PARAMETERS FOR CRUSHED ADALAT @ PA

Subject

1

ASBP (mm Hg)

t 9.0

MAXSBP (mm Hg)

f 35.3

MIN SBP (mm Hg)

1 16.3

MAX DBP (mm Hg)

71 -7

MIN DBP (mm Hg)

64.3

A DBP (mm Hg)

7.3

PHARMACODYNAMIC PARAMETERS GROUPED BY PHASE FOR T = O

Subiect SBP DBP MAP 1 HR Phase 1 Phase 2 Phase 1 Phase 2 Phase 1 Phase 2 Phase 1 Phase 2 142.3 135.3 77.0 71.7 98.8 92.9 71.0 60.3 123.0 110.0 67.7 72.3 86.1 84.9 71.3 75.3 131.7 120.3 73.7 73 .O 93 .O 88.8 64.7 61.3 120.7 123.0 82.3 84.0 95.1 97.0 68.7 68.0 1 . 3 1 1 5 . 3 71.3 75.7 88.7 88.9 53.7 56.7 117.3 115.7 68.0 72.0 84.4 86.6 64.3 77.0 131.3 125.0 80.0 87.3 97.1 99.9 73.0 70.0 152.3 155.7 113.0 113.0 126.1 127.3 68.0 68.7 113.3 109.7 65.3 61 .O 81.3 77.2 54.3 64.0 120.3 126.3 83.3 75.7 95.7 92.6 77.0 70.3 101.7 109.7 57.3 64.7 72.1 79.7 58.3 68.3 131.3 102.7 81.7 62.3 98.2 75.8 72.3 67.0 133.7 124.0 8 5 . 7 ' 75.3 101.7 91.6 64.0 65.7 1 13.3 107.3 77.0 70.7 89.1 82.9 52.7 39.7 1 12-7 114.0 77.7 72.7 89.3 86.4 73.7 71.7

Subject

1 2 3 4 5 6 7 8 9 10 I l 12 13 14 15 16 17 18 19

. SBP Phase t

24.3 Phase 2

19.0 Phase 1

8.0 10.3 7.0 11.0 7.7 6.7 6.0 24.3 2.3 19.7 0.0 14.0 20.7 3.0 9.7 7.3 16.0 7.0 3.3

DBP Phase 2

7.3 10.3 6.7

2 7.3 10.0 3.3 15.7 19.3 2.0 8 .O 8.7 8.3 22.0 3.0 7.7 t 2.7 10.3 12.7 6.7

Phase 1 12.2 14.0 11.2 7.2 9.1 7.7 4.4 22.4 3.2 18.4 6.7 15.1 20.2 3.9 9.1 9 .O 15.2 6.3 2.8

21.3 18.7

MAP Phase 2

11.3 9.4 7.1 15.0 9 .O 1.7

15.4 19.7 3.7 10.9 6.7 8.9

23.3 3.4 5.8 14.3 12.0 12.1 3.6

Phase 1 18.0 13.7 21.0 9.3 15.3 16.3 13.3 40.0 13.7 36.3 12.7 15.3 2 1.7 13.7 17.0 15.3 10.7 30.0 25.7

11.7 9.7

HR Phase 2

14.7 15.7 8.0

2 1 .O 17.0 9.7 19.0 33.7 16.3 13.7 13.0 15.7 17.0 15.3 15.3 18.0 16.7 28.3 30.7

3 -3 15.7 10.7 7.3

10.3 9.7 8.3 16.3

18.7 20.3 5.7 17.3 4.3

8.7 17.3 9.3

17.3 19.3 5.0 ,

10.0 27.0 2.3

15.0 14.0

8.7 19.0

13.7 9.3 20.7

17.3 14.7 4.0