Single-Dose and Multiple-Dose Pharmacokinetics and

Dose Proportionality of Intravenous and Intramuscular

HPbCD-Diclofenac (Dyloject) Compared with Other

Diclofenac Formulations

Fred Mermelstein,1,2 Douglas A. Hamilton,1,3 Curtis Wright,1,4 Peter G. Lacouture,5 Atulkumar

Ramaiya,6 and Daniel B. Carr1,7,*1Javelin Pharmaceuticals (now Hospira, Inc.), Cambridge, Massachusetts; 2The Leviathan Biopharma Group, Inc.,

Oncolupta, Inc., Newton, Massachusetts; 3New Biology Ventures, LLC, San Francisco, California; 4Rock Creek

Pharmaceuticals, Gloucester, Massachusetts; 5Global Clinical R&D and Medical Affairs, Hospira Inc., Lake

Forest, Illinois; 6Clinical Pharmacology, Hospira, Inc., Lake Forest, Illinois; 7Department of Anesthesiology,

Tufts Medical Center, Boston, Massachusetts

STUDY OBJECTIVE To evaluate single- and repeated-dose pharmacokinetics (PK) and dose proportional-ity of hydroxypropyl-b-cyclodextrin (HPbCD)-diclofenac compared with Voltarol after intravenous(IV) and intramuscular (IM) administration.

DESIGN Study 1: Single-dose randomized four-way crossover study. Study 2: Multiple-dose randomizedthree-way crossover study.

SETTING Clinical research center.SUBJECTS Healthy adult volunteers.INTERVENTION Study 1: Subjects received HPbCD-diclofenac and Voltarol, IV and IM, with a 5-day

washout between treatment periods. Study 2: Subjects received two doses of IV HPbCD-diclofenacand oral Cataflam once every 6 hours for four doses with a 48-hour washout period between treat-ment periods.

MEASUREMENTS AND MAIN RESULTS Study 1: IV HPbCD-diclofenac had a higher peak plasma concentra-tion (Cmax) and earlier time to reach maximum plasma concentration (Tmax), but equivalent plasmaexposure (area under the curve from time zero to t [AUC0–t]) to IV Voltarol. The geometric meanratio of HPbCD-diclofenac (IV) to Voltarol (IV) for AUC0–t was 106.27%. The geometric mean ratioof HPbCD-diclofenac (IM) to Voltarol (IM) for AUC0–t was 110.91%. The geometric mean ratio ofHPbCD-diclofenac (IV) to HPbCD-diclofenac (IM) for AUC0–t was 101.25%. The geometric meanratio of HPbCD-diclofenac (IM) to Voltarol (IV) for AUC0–t was 104.96%. Study 2: Cmax for diclofe-nac was 2904 and 6031 ng/ml after the first IV dose of 18.75 and 37.5 mg HPbCD-diclofenac,respectively, and was 3090 and 5617 ng/ml after the fourth dose, indicating no accumulation.Plasma exposures to 18.75 mg (866 ng�hour/ml) and 37.5 mg (1843 ng�hour/ml) IV HPbCD-dic-lofenac bracketed that of oral Cataflam 50 mg (1473 ng�hour/ml).

CONCLUSIONS Study 1: Bioavailability in terms of AUC after IV administration was equivalent forHPbCD-diclofenac compared with Voltarol and after IM administration of HPbCD-diclofenac andVoltarol. Bioavailability in terms of AUC after IM administration of HPbCD-diclofenac was equiva-lent to IV administration of HPbCD-diclofenac and IV administration of Voltarol. Study 2: HPbCD-diclofenac showed dose proportionality after single- and multiple-dose administration and noaccumulation of HPbCD-diclofenac. HPbCD-diclofenac was safe and well tolerated following IV andIM administration.

O R I G I N A L R E S E A R C H A R T I C L E S

KEY WORDS pharmacokinetics, analgesia, diclofenac, Dyloject, Voltarol, hydroxypropyl-b-cyclodextrin,intravenous, intramuscular, oral.(Pharmacotherapy 2013;33(10):1012--1021) doi: 10.1002/phar.1304

Balanced inhibition of both cyclooxygenase(COX)-1 and COX-2 by the nonsteroidal antiin-flammatory drug (NSAID) diclofenac allows it tobe highly effective in decreasing pain andinflammation.1, 2 Recent studies have furtherdemonstrated that diclofenac opens KCNQ2/3potassium channels and inhibits sensory neuro-nal depolarization, resulting in analgesia.3

Diclofenac has long been approved as safe andeffective for both acute and chronic pain througha variety of routes. However, no injectable dic-lofenac formulation is currently approved in theUnited States, in part due to the poor aqueoussolubility of diclofenac. Despite its proven effi-cacy,4–6 use of the current injectable diclofenacformulation (Voltarol) marketed in Europe, LatinAmerica, and other regions is limited by its cum-bersome preparation and administration require-ments. These include dilution, buffering withsodium bicarbonate, instability with consequentneed for immediate administration followingpreparation, and slow administration rate(30 minutes to 2 hours).7 In addition, this formu-lation uses two organic solvents, propylene glycoland benzyl alcohol, each of which is a known vas-cular irritant causing pain on injection8–10 or,

occasionally, local necrosis following intramuscu-lar (IM) injection (Nicolau syndrome).11

To overcome the poor aqueous solubility ofdiclofenac, we have used hydroxypropyl-b-cyclo-dextrin (HPbCD), a solubilizing agent currentlyused in several other pharmaceutical products.12, 13

HPbCD-diclofenac (diclofenac sodium solubi-lized with HPbCD, 37.5 mg/ml) was approvedfor marketing in October 2007 in the UnitedKingdom for the treatment or prevention ofpostoperative pain via intravenous (IV) or IMroutes.14 This ready-to-use HPbCD-diclofenacsolution is stable at room temperature anddesigned to minimize the complexity and risksresulting from multistep preparation and admin-istration of parenteral drugs.15 Because it lacksirritating organic solvents and may be adminis-tered as a single rapid IV bolus injection, theHPbCD-diclofenac formulation optimizes theanalgesic efficacy and safety profile of parenteraldiclofenac for acute pain.To evaluate the pharmacokinetics and safety of

the HPbCD-diclofenac formulation, we conductedtwo separate studies in healthy volunteers. Study1 used different routes of administration in com-parison with Voltarol. Study 2 evaluated singleand repeated administration of HPbCD-diclofenacin comparison with oral immediate-release dic-lofenac (Cataflam). The primary objective of thesestudies was to characterize the pharmacokineticprofile of HPbCD-diclofenac via different routesof administration compared with parenteral andoral formulations of diclofenac during single andrepeated dosing. The secondary objective was toassess the safety of HPbCD-diclofenac followingIV and IM administration.

Methods

Study Design

Study 1 was a single-dose randomized four-way crossover trial at Simbec Research Limited,United Kingdom. The protocol and informedconsent were reviewed and approved by theSouth East Wales Local Research Ethics Com-mission, Cardiff Wales, United Kingdom. Study2 was a multiple-dose randomized three-waycrossover study at the Parexel Clinical Pharma-

Data from this manuscript were previously presented atthe IASP World Congress on Pain, August 29 to September2, 2010, Montreal, QC, Canada.

This study was sponsored by Javelin Pharmaceuticals,Inc., Cambridge, MA (acquired in 2010 by Hospira, Inc.,Lake Forest, IL).

All authors performed this work as part of their employ-ment by Javelin Pharmaceuticals Inc. or Hospira Inc. D.B.Carr was the full-time chief medical officer, D.A. Hamiltonwas the full-time chief operating officer, F. Mermelsteinwas president, and C. Wright was the EVP of risk manage-ment and regulatory affairs for the study sponsor duringthe time of the study. P.G. Lacouture serves as medicaldirector, pain management, and A. Ramaiya serves as man-ager, clinical pharmacology, at Hospira Inc.

*Address for correspondence: Daniel B. Carr, Tufts Med-ical Center, no. 298, 800 Washington Street, Boston, MA02111; e-mail: daniel.carr@tufts.edu.� 2013 Hospira, Inc. Pharmacotherapy published by WileyPeriodicals, Inc. on behalf of the American College of Clin-ical Pharmacy.This is an open access article under the terms of theCreative Commons Attribution License, which permits use,distribution and reproduction in any medium, provided theoriginal work is properly cited.

PK OF INTRAVENOUS AND INTRAMUSCULAR HPbCD-DICLOFENAC Mermelstein et al 1013

cology Research Unit, Baltimore, Maryland. Theprotocol and informed consent were reviewedand approved by the Chesapeake ResearchReview, Inc., Columbia, Maryland. The studieswere conducted in accordance with the ethicalprinciples of the Declaration of Helsinki.

Subjects

Healthy male and female nonsmoker volun-teers 18 years of age or older were enrolled, withsimilar inclusion/exclusion criteria in studies 1and 2. Females were required to have a negativepregnancy test, be nonlactating, and practicecontraception. Subjects were excluded if theyhad any significant medical history or clinicallyrelevant laboratory test results; were serologicallypositive for the human immunodeficiency virus,hepatitis B, or hepatitis C; had hypersensitivityto NSAIDs; or were substance abusers.

Study Drugs

HPbCD-diclofenac 75 mg/2 ml (37.5 mg/ml)was administered by IV bolus (approximately15-second injection into a cannula in the sub-ject’s arm) or by deep intragluteal IM injection.Diclofenac sodium 75 mg/3 ml (25 mg/ml) (Vol-tarol; Novartis Pharmaceuticals UK, Ltd; Surrey,UK) was administered by 30-minute IV infusionand deep intragluteal IM injection. Diclofenacpotassium 50-mg tablets (Cataflam; NovartisPharmaceuticals Corp; East Hanover, NJ, USA)were administered orally.Subjects were screened 7 to 14 days prior to

randomization. Subjects were evaluated prior toeach visit to confirm compliance with inclusionand exclusion criteria.

Study Protocol

Study 1

Subjects were randomized to each of fourtreatments using a computer-generated randomsequence: A = one dose of HPbCD-diclofenac75 mg/2 ml, IV bolus, delivered as previouslydescribed; B = one dose of HPbCD-diclofenac75 mg/2 ml, deep intragluteal IM injection;C = one dose of Voltarol 75 mg/3 ml, 30-minuteIV infusion; and D = one dose of Voltarol75 mg/3 ml, deep intragluteal IM injection. Fourtreatment sequences were utilized to randomizesix subjects per sequence. There was a minimum5-day washout between treatments.

Study 2

Subjects were randomized to receive each ofthree treatments in a sequence determined by acomputer-generated randomization list:A = HPbCD-diclofenac 18.75 mg IV bolus;B = 37.5 mg IV bolus injection, delivered as pre-viously described; and C = Cataflam 50 mgorally. Each subject received four doses of eachof these three diclofenac formulations at 6-hourintervals separated by a 48-hour washout. Studydrug administration occurred on days 1, 4, and 7.

Sample Collection

Study 1

Venous blood samples were collected via anindwelling catheter or venipuncture immediatelybefore and at 3, 6, 10, 20, 30, 35, 40, 45, 50,55, 60, 75, 90, and 105 minutes and 2, 3, 4, 6,and 8 hours after each dose of HPbCD-diclofe-nac or Voltarol.

Study 2

Venous blood samples were collected immedi-ately before and for 30 hours after the first doseof IV HPbCD-diclofenac or oral Cataflam. Bloodsamples were obtained via an indwelling IV can-nula or venipuncture on days 1, 4, and 7, immedi-ately before and at 5, 10, 20, 30, and 45 minutesand 1, 1.5, 2, 2.5, 3, 4, and 6 hours after the firstdose. Later samples were taken immediatelybefore the third and fourth dose and at 5, 10, 20,30, and 45 minutes and 1, 1.5, 2, 2.5, 3, 4, 6, 8,10, and 12 hours after the fourth dose.Blood samples from both studies were col-

lected in 5-ml heparinized Vacutainers (BD,Franklin Lakes, NJ, USA) and centrifuged imme-diately after collection. The plasma was decantedinto polypropylene tubes and stored at �20°Cuntil assay.

Assay Methodology for Study 1 and Study 2

Diclofenac plasma concentrations were mea-sured by liquid chromatography with tandemmass spectrometry detection, a method previouslyvalidated for the detection of diclofenac in humanplasma and urine.16 The assay used atmosphericpressure ionization with turbo ion spray followedby multiple reaction monitoring of the character-istic deprotonated molecular ion to product-iontransitions for diclofenac and internal standard.This assay was linear from 25 to 30,000 ng/ml. Its

1014 PHARMACOTHERAPY Volume 33, Number 10, 2013

precision ranged from 7.4% to 8.6%, and its accu-racy ranged from 100% to 107%.

Pharmacokinetic Analyses for Study 1 and Study2

Pharmacokinetic parameters were calculatedusing noncompartmental analysis. Only thoseplasma concentrations equal to or greater thanthe lower limit of quantitation (LOQ; 25.0 ng/ml) were used in the analyses. Actual samplingtimes were used in all pharmacokinetic analyses.Per protocol times were used to calculate meanplasma concentrations for graphical displays.Cmax and Tmax were taken directly from the

data. The elimination rate constant, kz, was cal-culated as the negative of the slope of the termi-nal log-linear segment of the plasmaconcentration-time curve. The data used foreach subject and treatment were determined byvisual inspection of a semilogarithmic plot ofconcentration versus time. Elimination half-life(t½) was calculated as

t1=2 ¼ 0:693

kz

Area under the curve (AUC0–t) from zero to thefinal sample with a concentration ≥LOQ (AUC0–t)was calculated using the linear trapezoidalmethod and extrapolated to infinity using

AUC0�1 ¼ AUC0�t þ Ctf

kz

where Ctf is the final concentration ≥LOQ.For each treatment in study 2, the following

pharmacokinetic parameters were calculatedusing noncompartmental analysis:

• First dose: Cmax, Tmax, AUC(0–t), and t½• Fourth dose: Cmax, Tmax, AUC(0–6), and t½

Safety

Safety assessments included adverse event(AE) monitoring, physical examinations, clinicallaboratory tests, vital signs, and electrocardio-grams (ECGs). Thrombophlebitis assessment bythe clinical staff of the subject’s IV site at 4 and8 hours following IV administration wasincluded after IV bolus administration. A 6-pointthrombophlebitis grading scale17 was used(0 = no reaction; 1 = tenderness along the vein;2 = continuous tenderness or pain with redness;3 = palpable swelling or thrombosis within thelength of the cannula; 4 = palpable swelling or

thrombosis beyond the length of the cannula;5 = as for grade 4, with overt infection).

Statistical Analyses

Study 1

Statistical sample size calculations were con-ducted using data from previous clinical studies.Within-subject coefficients of variation for natu-ral log-transformed AUC0–t and AUC0–∞ wereboth approximately 13%, indicating that samplesizes of 16–24 subjects should provide 80%power to obtain 90% confidence intervals within80% ? 125% range if the true differencebetween observations for the different formula-tions was 5% or less.Comparison of AUC0–t and AUC0–∞ between

the HPbCD-diclofenac (test) and Voltarol (refer-ence) treatments was conducted on natural loga-rithms of the primary data using an analysis ofvariance (ANOVA) model with sequence, subjectwithin sequence, treatment, and period as classi-fication variables.18 Sequence was tested usingsubject within sequence as the error term; allother terms were tested using mean squarederror. Confidence intervals (90%) were con-structed for the ratios (test to reference) of thetwo parameters using the log-transformed dataand the one-sided t-test procedures. The pointestimates and confidence limits were exponenti-ated back to the original scale.

Study 2

The analysis used descriptive statistics (meanand standard deviation). Pharmacokinetic parame-ters were compared for different doses (18.75 and37.5 mg) and multiple-dose administrations. Cmax

and AUC(inf) for the first dose and Cmax andAUC(0–6) for the fourth dose were compared acrosstreatments using ANOVA with subject and dosenumber as classification variables, using the natu-ral logarithm of the data.18 Pharmacokinetic datafrom both studies were analyzed using WinNonlinv.3.3 (Pharsight, Mountain View, CA, USA).

Results

Subjects

Study 1

Twenty-four healthy subjects were enrolled.Among them, 22 completed all four phases and

PK OF INTRAVENOUS AND INTRAMUSCULAR HPbCD-DICLOFENAC Mermelstein et al 1015

were included in the pharmacokinetic analysisand in the statistical comparisons for which theyhad data for all treatments.

Study 2

Thirty-six healthy subjects were enrolled. All36 subjects completed the pharmacokinetic com-ponent of the study and were included in thepharmacokinetic analysis.

Pharmacokinetics

Study 1

Consistent with the distinct administrationprotocols of rapid IV bolus versus 30-minuteinfusions, mean plasma concentration-time pro-files after IV administration differed betweenHPbCD-diclofenac and Voltarol (Table 1,Figure 1). HPbCD-diclofenac was administeredIV over 15 seconds and had a mean Cmax

approximately 4-fold higher (21,524 ng/ml) thanthe Cmax for Voltarol (5668 ng/ml) administeredIV over 30 minutes. Following IV administrationof HPbCD-diclofenac, median Cmax occurred at0.05 hours versus 0.5 hours for Voltarol. Themean half-life (t½) of diclofenac was equivalentfor both formulations, averaging1.17 � 0.32 hours for IV HPbCD-diclofenac and1.23 � 0.31 hours for IV Voltarol.Overall exposures to diclofenac for HPbCD-

diclofenac and Voltarol were equivalent (meanAUC0–∞ 4420 � 1636 ng�hour/ml and4055 � 694 ng�hour/ml, respectively) with apoint estimate and 90% confidence interval (CI)for the geometric mean ratio of HPbCD-diclofe-nac (IV) to Voltarol (IV) of 105.49% (90% CI98.88–112.53), demonstrating comparable bio-availability in terms of AUC (Table 2).

The mean Cmax (2569 ng/ml) after IMHPbCD-diclofenac was higher compared withVoltarol IM (Cmax 1541 ng/ml; Table 1). Thehigher Cmax with HPbCD-diclofenac comparedwith Voltarol after IM administration indicatesa more rapid early exposure profile. The medianTmax following IM administration was0.642 hours for HPbCD-diclofenac and0.792 hours for Voltarol. The mean values forHPbCD-diclofenac and Voltarol for AUC0–∞were 4304 � 908 ng�hour/ml and 3932 �627 ng�hour/ml, respectively, with a pointestimate of 107.91% (90% CI 101.05–115.24),demonstrating equivalent bioavailability in termsof AUC after IM administration (Table 2,Figure 2).The mean Cmax for Voltarol infused IV over

30 minutes was 5668 ng/ml compared with aCmax of 2569 ng/ml for IM HPbCD-diclofenac.The Tmax for IV Voltarol was 0.5 hours versus0.642 hours for IM HPbCD-diclofenac. Based on

Table 1. Pharmacokinetic Parameters After Intravenous and Intramuscular Administration of 75 mg HPbCD-Diclofenacand 75 mg Voltarol to Healthy Volunteers

ParameteraIntravenous Intramuscular

HPbCD-Diclofenac Bolus Voltarol Infusion HPbCD-Diclofenac Voltarol

Cmax (ng/ml) 21,524 � 30,705 b 5668 � 974 2569 � 1092 1541 � 419Tmax (hrs) 0.050 0.500 0.642 0.792AUC0–t (ng�hr/ml) 4363 � 1600 3970 � 690 4237 � 869 3754 � 609AUC0–∞ (ng�hr/ml) 4420 � 1636 4055 � 694 4304 � 908 3932 � 627t1/2 (hrs) 1.17 � 0.32 1.23 � 0.31 1.17 � 0.31 1.71 � 0.29

Cmax = maximum observed plasma concentration; Tmax = time at which Cmax is observed; AUC(0–t) = AUC up to the last quantifiable concen-tration; AUC0–∞ = AUC from time zero to infinite time; t½ = apparent elimination half-life.aMean � SD except for Tmax for which the median is reported.bValue is higher than expected because one subject had a plasma concentration at the 3-minute blood draw time point that was 10-foldhigher than expected. The clinical site deems it possible that the same cannula was used for drug administration and for the 3-minute blooddraw for that subject.

Figure 1. Plasma concentrations of diclofenac following IVadministration of diclofenac-HPbCD (HPbCD-diclofenac)and diclofenac (Voltarol).

1016 PHARMACOTHERAPY Volume 33, Number 10, 2013

this pharmacokinetic data, the IM administrationof HPbCD-diclofenac offers comparable delivery.Overall exposures for HPbCD-diclofenac (IV)

and HPbCD-diclofenac (IM) were equivalent(AUC0–∞ 4420 � 1636 ng�hour/ml and 4304 �908 ng�hour/ml, respectively). The point esti-mate and 90% CI for the geometric mean ratio

of HPbCD-diclofenac (IV) to HPbCD-diclofenac(IM) was 100.76% (90% CI 94.24–107.74)(Table 3), indicating equivalent exposure.Overall exposures for HPbCD-diclofenac (IM)

and Voltarol (IV) were equivalent (AUC0–∞4304 � 908 ng�hour/ml and 4055 � 694ng�hour/ml, respectively), with a point estimateand 90% CI of 104.69% (90% CI 98.03–111.79)(Table 3).The mean t1/2 following administration of IV

HPbCD-diclofenac was 1.17 � 0.32 hours ver-sus 1.17 � 0.31 hours after IM HPbCD-diclofe-nac, suggesting similar disposition profiles withthis formulation by both IV and IM routes.

Study 2

Study 2 compared the pharmacokinetics ofHPbCD-diclofenac following IV administrationof single and multiple doses of 18.75 and37.5 mg versus oral Cataflam (Figure 3). Asexpected, mean plasma concentrations weremaximal immediately after IV dosing. OralCataflam exhibited slower absorption, with amedian Tmax of 1.5 hours (Table 4). The Cmax

following the first IV dose of HPbCD-diclofenacapproximately doubled from a mean of 2904–6031 ng/ml for 18.75 versus 37.5 mg. TheAUC0–∞ also approximately doubled from amean of 898–1859 ng�hour/ml across IV dosesof 18.75–37.5 mg of HPbCD-diclofenac, demon-strating dose-proportional pharmacokinetics forIV HPbCD-diclofenac. The Cmax following the

Table 2. Bioavailability of HPbCD-Diclofenac and VoltarolAfter Intravenous (IV) and Intramuscular (IM) Adminis-tration to Healthy Volunteers

Parameter Geometric Mean Ratio90% Confidence

Intervala

HPbCD-diclofenac (IV) vs Voltarol (IV)AUC0–t 106.27 99.69 ? 113.28AUC0–∞ 105.49 98.88 ? 112.53HPbCD-diclofenac (IM) vs Voltarol (IM)AUC0–t 110.91 103.94 ? 118.34AUC0–∞ 107.91 101.05 ? 115.24aBased on analysis of natural log-transformed data. Geometricmean ratio of HPbCD-diclofenac to Voltarol.

Table 3. Bioavailability Based on AUC of HPbCD-diclofe-nac (Intravenous [IV]) versus HPbCD-Diclofenac (Intra-muscular [IM]) and HPbCD-Diclofenac (IM) versusVoltarol (IV)

Parameter Geometric Mean Ratio90% Confidence

Intervala

HPbCD-diclofenac (IV) vs HPbCD-diclofenac (IM)AUC0–t 101.25 94.86 ? 108.06AUC0–∞ 100.76 94.24 ? 107.74HPbCD-diclofenac (IM) vs Voltarol (IV)AUC0–t 104.96 98.36 ? 112.00AUC0–∞ 104.69 98.03 ? 111.79aBased on analysis of natural log-transformed data.

Figure 2. Plasma concentrations of diclofenac following IMadministration of diclofenac-HPbCD (HPbCD-diclofenac)and diclofenac (Voltarol).

Figure 3. Plasma concentrations of diclofenac followingadministration of multiple doses of IV diclofenac-HPbCD(HPbCD-diclofenac) and diclofenac potassium (Cataflam)every 6 hours. Concentrations were measured after the firstand fourth doses.

PK OF INTRAVENOUS AND INTRAMUSCULAR HPbCD-DICLOFENAC Mermelstein et al 1017

fourth IV dose was 3090 g/ml and 5617 ng/ml,for 18.75 and 37.5 mg, respectively. AUC(0–6)

following the fourth dose of 18.75 and 37.5 mgwere 935 and 1839 ng�hour/ml, respectively.The Cmax and AUC following the first andfourth doses were similar, suggesting no accu-mulation of IV HPbCD-diclofenac. The calcu-lated accumulation factor based on half-life wasclose to 1, indicating a lack of accumulationduring successive doses given every 6 hours,approximately 3.5 9 t½.Plasma exposures to IV HPbCD-diclofenac

18.75 mg (866 ng�hour/ml) and 37.5 mg(1843 ng�hour/ml), as measured by AUC uncor-rected for dose, bracketed that after administrationof the first oral Cataflam 50 mg dose (1473 ng�hr/ml). This is consistent with the bioavailability oforal Cataflam, which was 64.1% after the first doseand 54.6% after the fourth dose.The Cmax after the fourth dose of oral Cata-

flam 50 mg was 851 ng/ml compared with aCmax of 1246 ng/ml following the first dose. TheAUC following the first dose was 1473 ng�hour/ml compared with 1350 ng�hour/ml followingthe fourth dose of Cataflam, suggesting variabil-ity in diclofenac’s oral absorption. The IV pro-files of HPbCD-diclofenac were similar andconsistent following the first and fourth dosecompared with a substantial decrease in Cmax

from the first to the fourth dose of Cataflam.

Safety

Study 1

No serious AEs occurred during the study.There were no clinically significant changes inclinical laboratory tests, ECGs, or vital signsreported. A total of eight treatment-emergentAEs were reported by five subjects (HPbCD-dic-lofenac: two subjects; Voltarol: three subjects).

The specific AEs for Voltarol included anemia,dizziness, headache, sweating, and vasovagalattack; for HPbCD-diclofenac they included dys-geusia, postural dizziness, and headache. Of thereported adverse events, only one event (dysgeu-sia following IV administration) was considered“related” to the study drug. All other AEs wereconsidered “not related” or “unlikely to berelated” to the study drug and were mild ormoderate in severity.The thrombophlebitis assessment revealed that

one subject (1 of 23, 4.3%) given HPbCD-diclofe-nac had mild irritation (1 = tenderness along thevein) at the 4- and 8-hour time points. Similarly,one subject (1 of 24, 4.2%) had mild irritation(1 = tenderness along the vein) only at the 4-hourtime point following Voltarol administration.

Study 2

There were no serious AEs, and none of thesubjects were discontinued from the study dueto an AE. A total of 14 treatment-emergent AEswere reported by seven subjects; all were mild,resolved spontaneously, and most were unre-lated to study treatments. Treatment-related AEsincluded three mild gastrointestinal events andone instance of mild injection site pain.None of the chemistry or hematology changes

were considered clinically significant. Therewere no clinically significant changes in vitalsigns. There were no clinically significant find-ings or observable differences between treatmentsequences for quantitative or qualitative ECGparameters.

Discussion

HPbCD, a cyclic glucose-derived oligomerconsisting of linked a-1,4-glucose units, wasused to enhance the solubility of diclofenac for

Table 4. Summary of Pharmacokinetic Parameters after Single-and Repeated-Dose Administration of Intravenous HPbCD-Diclofenac and Cataflam to 36 Healthy Volunteers

Parametera

HPbCD-Diclofenac(First Dose)

HPbCD-Diclofenac(Fourth Dose)

Cataflam(First Dose) Cataflam (Fourth Dose)

18.75 mg 37.5 mg 18.75 mg 37.5 mg 50 mg 50 mg

Cmax (ng/ml) 2904 � 661 6031 � 1178 3090 � 1029 5617 � 1799 1246 � 732 851 � 462Tmax (hrs) 0.083 0.083 0.083 0.083 1.5 1.49AUC0–6 (ng�hr/ml) 866 � 221 1843 � 394 935 � 203 1839 � 506 1473 � 488 1350 � 601AUC0–∞ (ng�hr/ml) 898 � 231 1859 � 376 – – 1562 � 519 –t1/2 (hrs) 1.39 � 0.29 1.44 � 0.27 1.82 � 0.48 2.29 � 0.63 1.28 � 0.27 2.80 � 0.66

Cmax = maximum observed plasma concentration; Tmax = Time at which Cmax is observed; AUC(0–t) = area under the curve (AUC) up to thelast quantifiable concentration; AUC0–∞ = AUC from time zero to infinite time; t½ = apparent elimination half-life.aMean � SD except for Tmax for which the median is reported.

1018 PHARMACOTHERAPY Volume 33, Number 10, 2013

injection.19 Compared with the previous formu-lation (Voltarol), this approach allows a reduc-tion in dosing volume and lessened irritationprovoked by the nonphysiologic pH and organicsolvents.20 HPbCD has likewise been used toenhance the solubility of poorly soluble drugssuch as the marketed antifungal itraconazole8

and a novel formulation of propofol underdevelopment.9 When diclofenac is solubilizedwith HPbCD, a therapeutic dose of diclofenac isavailable in a smaller volume, 75 mg/2 ml versus75 mg/3 ml as in Voltarol. Furthermore, whenVoltarol is to be administered IV, it must first bediluted to 50 to 100 ml.The effects of route of administration on phar-

macokinetics of this novel formulation wereexamined by comparing IV and IM administra-tion, and by evaluating IV versus a dose-adjustedoral comparison. The first comparison was ofthe new formulation versus the preexisting prod-uct when both were administered IV. We foundthat AUC0–t and AUC0–∞ were equivalentbetween HPbCD-diclofenac and Voltarol after IVadministration. The 90% CIs for the geometricmean ratios of HPbCD-diclofenac to Voltarolwith respect to AUC0–t and AUC0–∞ were wellwithin the accepted 80–125% equivalence win-dow for bioavailability. Thus HPbCD-diclofenacand Voltarol have equivalent bioavailability fol-lowing IV administration. However, Cmax wasnot used in this study to assess equivalence, asthe two products differed with respect to rate ofadministration. Current labeling for Voltarolindicates that the dose be administered over a30-minute infusion, whereas HPbCD-diclofenacis administered as a rapid IV bolus. As would beexpected, Cmax was higher and Tmax earlier afterHPbCD-diclofenac administration comparedwith Voltarol. This difference may contribute tothe clinical observation of a more rapid onset ofanalgesia for HPbCD-diclofenac than Voltarol.21

Despite the higher Cmax, there was no increasedsafety risk based on AEs, laboratory tests, andvital signs. These data corroborate a safety meta-analysis of seven single-dose clinical trials22 thatfound the incidence of thrombophlebitisobserved following IV HPbCD-diclofenac treat-ment was 1.2% versus 6.5% following IV Volta-rol.When compared for a similar route of admin-

istration (IM), AUC0–t and AUC0–∞ were equiva-lent for HPbCD-diclofenac and Voltarol. The90% CIs for the geometric mean ratios ofHPbCD-diclofenac to Voltarol with respect toAUC0–t and AUC0–∞ were within the 80–125%

equivalence window for bioavailability. ThusHPbCD-diclofenac and Voltarol have equivalentbioavailability following IM administration.Finally, the route and process of administra-

tion can be examined for IM HPbCD-diclofenacand IV Voltarol. Of note is that the pharmacoki-netics for the different formulations and routeswere similar. The longer t1/2 following IMadministration could be potentially attributed tothe flip-flop phenomenon.23 The flip-flop phe-nomenon occurs when the process of absorptionis the rate-limiting factor in the overall disposi-tion of the drug. The terminal t1/2 under flip-flop condition reflects the rate and extent ofabsorption and is not a true t1/2; for Voltarol itcan be potentially attributed to the formulationcharacteristics that result in erratic absorption.The lack of flip-flop phenomenon after IMadministration of HPbCD-diclofenac comparedwith Voltarol could be attributed to superior sol-ubilization using HPbCD versus organic sol-vents. Due to the extended infusion time for theIV Voltarol, Cmax was lower compared with IMHPbCD-diclofenac. Furthermore, the AUCs wereequivalent.When developing dosing guidelines, it is

important to establish proportionality using thepharmacokinetic profile of a product. Two dosesof HPbCD-diclofenac (18.75 and 37.5 mg)within the therapeutic range were examined.The pharmacokinetics were dose proportionalafter IV administration of both doses, indicatingthat Cmax and AUC were dose proportional.The plasma exposures to 18.75 and 37.5 mg

IV HPbCD-diclofenac, as measured by AUCuncorrected for dose, bracketed that afteradministration of oral Cataflam 50 mg, thusoffering the option for transition of therapy fromIV for inpatients to oral following their releasehome from the hospital.Most products to treat acute postoperative

pain require multiple doses, raising concern thatrepeated dosing many lead to increasing expo-sure secondary to frequent dosing or a reducedmetabolic clearance. However, we found thatoverall, pharmacokinetic parameters after singleand multiple doses did not differ; nor was thereevidence for accumulation of diclofenac after IVadministration of HPbCD-diclofenac every6 hours for four doses. Diclofenac is predomi-nantly eliminated via hepatic biotransformationto 4-hydroxy-diclofenac as the major metabolite,a reaction catalyzed by the cytochrome P450enzyme CYP2C9. The lack of accumulation ofdiclofenac following IV and IM administration

PK OF INTRAVENOUS AND INTRAMUSCULAR HPbCD-DICLOFENAC Mermelstein et al 1019

reduces the potential for clinical drug-druginteractions with substrates and inhibitors ofCYP2C9, a genetically polymorphic enzyme.IV bolus administration of HPbCD-diclofenac

did not raise safety concerns. HPbCD-diclofenacadministered as 18.75 and 37.5 mg IV bolusesevery 6 hours over 24 hours was safe and welltolerated.Recent clinical trials evaluating the use of rapid

bolus injections of HPbCD-diclofenac have indi-cated a faster onset of analgesia compared withother NSAIDs, which is consistent with the phar-macokinetic profile of this new formulation dem-onstrated in the current study. In two separatedouble-blind placebo-controlled trials in patientsundergoing third-molar extraction, HPbCD-dic-lofenac had a faster onset of pain relief than eitherVoltarol21 or ketorolac.24 More recently, HPbCD-diclofenac showed a faster onset of action than IVketorolac in a population of patients havingundergone orthopedic surgery.25

The lower incidence of thrombophlebitis withHPbCD-diclofenac compared with Voltarol andsubsequent reduced need for treatment ofadverse events, as well as HPbCD-diclofenac’slack of need for reconstitution, dilution, and buf-fering prior to each dose compared with Voltarolprovide support for potential cost savings withHPbCD-diclofenac compared with Voltarol.26

Conclusion

HPbCD-diclofenac, a novel formulation of dic-lofenac with convenience in both IV and IM dos-ing, demonstrated a higher peak plasmaconcentration (Cmax) and earlier time to peakplasma concentration (Tmax), as compared withVoltarol. Overall plasma exposures for HPbCD-diclofenac and Voltarol were equivalent. HPbCD-diclofenac was safe and well tolerated, with fewAEs reported. Lack of accumulation and linearpharmacokinetics of HPbCD-diclofenac were alsodemonstrated, which could potentially provideadded benefits in patients with complex analgesicregimens or receiving multimodal analgesia.

Acknowledgment

We thank William G. Kramer (Kramer Con-sulting, LLC, North Potomac, MD) for pharma-cokinetic analytic guidance.

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