CLINICAL PHARMACOKINETICS - pcp.nihtraining.com · CLINICAL PHARMACOKINETICS Juan J.L. Lertora,...
Transcript of CLINICAL PHARMACOKINETICS - pcp.nihtraining.com · CLINICAL PHARMACOKINETICS Juan J.L. Lertora,...
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CLINICAL PHARMACOKINETICS Juan J.L. Lertora, M.D., Ph.D.
Director
Clinical Pharmacology Program
Office of Clinical Research Training and Medical Education
National Institutes of Health Clinical Center
Septemeber 8, 2011
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USES OF PHARMACOKINETICS
Basis for rational dose selection in therapeutics Development and evaluation of new drugs Basic studies of drug distribution (PET Scan)
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Target Concentration Strategy
ESTIMATE INITIAL DOSE
TARGET LEVEL
LOADING DOSE
MAINTENANCE DOSE
Down arrow
BEGIN THERAPY
Down arrow
ASSET THERAPY
PATIENT RESPONSE
DRUG LEVEL
Down arrow
REFINE DOSE ESTIMATE – Arrow back to Assess Therapy
ADJUST DOSE (return to Assess Therapy)
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RATIONALE FOR
PLASMA LEVEL MONITORING
Flowchart for rationale for plasma level monitoring beginning with
Prescribed dose and ending in effect.
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FIRST DESCRIPTION OF THERAPEUTIC DRUG
MONITORING
Copy of this article from
Wuth O. JAMA
1927;88:2013-17.
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RADIOIMMUNOASSAY
Photo of Rosalyn Sussman Yalow – 1977 Nobel Laureate
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First Academic Clinical Drug Analysis Lab
Arthur J. Atkinson, Jr., M.D.
Northwestern Memorial Hospital
Chicago, Illinois
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GAS LIQUID CHROMATOGRAPHY
Photo of gas liquid chromatography
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HIGH PERFORMANCE
LIQUID CHROMATOGRAPHY
Photo of high performance liquid chromatograph
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FLUORESCENCE POLARIZATION
IMMUNOASSAY
Photo of TDX FPIA Analyzer
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DRUG CANDIDATES FOR TDM
Low therapeutic index No physiologic or therapeutic endpoints to guide dosage Pharmacokinetics vary widely between individuals Need to monitor adherence?
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EFFECT OF ADHERENCE RATE ON
OUTCOME IN HIV INFECTED PATIENTS
Bar chart showing virologic failure rates and percent of adherence rates. Adherence
improves treatment outcome.
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INDICATIONS for Measuring Blood Levels
To evaluate suspected toxicity To evaluate actual or potential lack of therapeutic efficacy To monitor prophylactic therapy To guide dose adjustment
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Target Concentration Strategy
Estimate initial dose
Target level
Loading dose
Maintenance dose
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DIGOXIN Levels in TOXIC and NONTOXIC Patients*
Chart showing that from Smith TW and Haber E. J Clin Invest 1970;49-2377-86
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DIGOXIN: Factors Influencing
OUTCOME in “GREY ZONE”
Up Arrow - Risk of toxicity in patients with coronary heart disease, hypoxemia,
and/or hypokalemia, hypomagnesemia
Down Arrow - ECG evidence of toxicity if concurrent therapy with antiarrhythmic
drugs
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TRADITIONAL Guidelines
for DIGOXIN Levels
THERAPEUTIC RANGE: 0.8 - 1.6 ng/mL
POSSIBLY TOXIC LEVELS: 1.6 - 3.0 ng/mL
PROBABLY TOXIC LEVELS: greater than 3.0 ng/mL
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SURVIVAL as a function of DIGOXIN LEVEL
measured after 1 Month Rx*
Chart illustrating that from Rathore SS, et Al. JAMA 2003;289:871-8
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PROPOSED Range of DIGOXIN LEVELS for
OPTIMAL THERAPY in CHF
New Therapeutic Range: 0.5 - 0.9 ng/mL
Benefit results from INHIBITION OF SYMPATHETIC NERVOUS SYSTEM
rather than (up arrow) INOTROPY
BUT DIGOXIN DOSES PRESCRIBED FOR PATIENTS WITH THIS
RANGE OF DIGOXIN LEVELS SHOULD HAVE BEEN ASSOCIATED
WITH HIGHER LEVELS?
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DIGOXIN DOSES for Patients with Levels of 0.5 - 0.8 ng/mL
Bar chart showing percent of patients taking four different daily doses of
Digoxin from Rathore SS, et al. JAMA 2003,289:871-8
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Target Concentration Strategy
ESTIMATE INITIAL DOSE
TARGET LEVEL
LOADING DOSE
MAINTENANCE DOSE
BASED ON CONCEPT OF DISTRIBUTION VOLUME
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DIGOXIN LEVELS after IV Dose
Chart illustrating this showing the distribution phase and the elimination
phase
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Initial Digitalization
Formula relating initial dose, initial digoxin concentration and
apparent volume of distribution.
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3 DISTRIBUTION VOLUMES
equation
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DISTRIBUTION DELAYS ONSET
of DIGOXIN Chronotropic Action*
Chart
Gold H, et al. J Pharmacol Exp Ther 1953;109:45-57
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DISTRIBUTION DELAYS ONSET of
DIGOXIN Inotropic Action*
Chart
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Target Concentration Strategy
Estimate initial dose
Target level
Loading dose
Maintenance dose
Based on concepts
Elimination half life
and clearance
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ELIMINATION HALF-LIFE
ELIMINATION HALF-LIFE IS THE TIME REQUIRED FOR THE PLASMA
CONCENTRATION (OR TOTAL BODY STORES) OF A DRUG TO FALL TO
HALF OF THE CONCENTRATION (OR AMOUNT) PRESENT AT SOME
PREVIOUS TIME.
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ELIMINATION PARAMETERS
EQUATION
t ½ = elimination half life
k = elimination rate
CLE = elimination clearance
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Maintenance Digoxin Therapy
Formula relating maintenance dose to daily digoxin loss from the
body.
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DIGOXIN CUMULATION
Formula showing exponential accumulation of digoxin.
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CUMULATION FACTOR
equation
τ = dose interval
k = elimination rate constant
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ELIMINATION RATE CONSTANT
equation
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LOADING & MAINTENANCE DOSES
Chart showing Digoxin levels over time as a function of loading
and maintenance dosing.
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TIME-COURSE OF DIGOXIN CUMULATION
Chart showing plasma Digoxin levels over time.
Steady-state levels take longer to be reached in patients with
uremia.
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DIGOXIN CASE HISTORY
A 39 year-old man with mitral stenosis was hospitalized for mitral valve
replacement (October 1981). He had a history of chronic renal failure
resulting from interstitial nephritis and was maintained on
hemodialysis. His mitral valve was replaced with a prosthesis and
digoxin therapy was initiated postoperatively in a dose 0.25 mg/day.
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DIGOXIN CASE HISTORY (cont.)
Two weeks later, he was noted to be unusually restless in the evening.
The following day, he died shortly after he received his morning Digoxin
dose. Blood was obtained during an unsuccessful resuscitation attempt,
and the measured plasma Digoxin concentration was
6.9 ng/mL.
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Target Concentration Strategy
ESTIMATE INITIAL DOSE
TARGET LEVEL
LOADING DOSE
MAINTENANCE DOSE
Down arrow
BEGIN THERAPY
Down arrow
ASSESS THERAPY
PATIENT RESPONSE
DRUG LEVEL
Down Arrow
REFINE DOSE ESTIMATE
Down arrow
ADJUST DOSE (Arrow back to Assess Therapy)
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Target Concentration Strategy
ESTIMATE INITIAL DOSE
TARGET LEVEL
LOADING DOSE
MAINTENANCE DOSE
Down arrow
BEGIN THERAPY
Down arrow
ASSESS THERAPY
PATIENT RESPONSE
DRUG LEVEL
Down Arrow
REFINE DOSE ESTIMATE
Down arrow
ADJUST DOSE (Arrow back to Assess Therapy)
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PHARMACOKINETIC ANALYSIS OF
DIGOXIN CASE HISTORY
ESTIMATED T1/2:
4.3 days (k = 0.16 day-1)
TIME TO 90% STEADY STATE:
3.3 x 4.3 = 14.2 days
STEADY STATE PEAK LEVEL:
6.2 ng/mL (post distribution phase)
MEASURED LEVEL:
6.9 ng/mL (pre distribution)
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STEADY STATE CONCENTRATION
Continuous infusion equation
Intermittent Dosing equation
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STEADY STATE CONCENTRATION
Not determined by loading dose
Mean steady state concentration not determined by Vd
Peak and trough are affected by Vd
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Vd AFFECTS PEAK AND TROUGH
BUT NOT MEAN LEVELS
Chart illustrating this
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FOR MOST DRUGS, Css IS PROPORTIONAL TO DOSE
(Dosing Rate)
Continuous Infusion equation
Intermittent dosing equation
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STEADY STATE CONCENTRATION
NOT DETERMINED BY LOADING DOSE
MEAN STEADY STATE CONCENTRATION
NOT DETERMINED BY Vd
CHANGES IN MAINTENANCE DOSE
RESULT IN DIRECTLY PROPORTIONAL
CHANGES IN Css FOR MOST DRUGS
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PHARMACOKINETIC MODELS
WHAT PHARMACOKINETIC PARAMETERS ARE PRIMARY?
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SINGLE COMPARTMENT MODEL
Example diagram
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ELIMINATION HALF-LIFE
equation
Therefore, t ½ is t a primary pharmacokinetic parameter
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3 DISTRIBUTION VOLUMES
equations
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Some Drugs are NOT Eliminated by First Order
Kinetics
Phenytoin (Dilantin)
Ethyl Alcohol
Acetylsalicylic Acid (aspirin)
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Phenytoin Hydroxylation
Chemical structure
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Chart
Plasma DPH (mcg/ml)
DPH elimination (mg/day)
Urine Creatine (mg/day)
DPH Dose (mg/day)
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Phenytoin Kinetics
In Normal Subjects Chart depicting Phenytoin Kinetics.
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Steady State Equations First Order Kinetics equation
Michealis – Menten kinetics equation
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Relationship of Plasma Level to Phenytoin Dose* Phenytoin Dose Plasma Level
(mg/day) µg/mL
300 10
400 20
500 30
(THERAPEUTIC RANGE: 10 – 20 μg/mL)
*From: Kutt H, McDowell F: J Am Med Assoc 1968:203:969-72
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Patient who Became Toxic on a
Phenytoin Dose of 300 mg/day
Chart illustrating this.
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Phenytoin Case History
After inpatient evaluation for a generalized seizure, a 28-year-old
woman was discharged on phenytoin therapy at a dose of 300 mg/day.
After 5 days of therapy, she presented to the hospital’s emergency
department with marked ataxia. Her phenytoin plasma concentration
was found to be 27 μg/mL. She was sent home on a reduced phenytoin
dose of 200 mg/day.
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Phenytoin Case History (cont.)
Two days later, she returned to the emergency department with more
severe ataxia. Her phenytoin plasma concentration was now 32 μg/mL.
Non-compliance was suspected but a clinical pharmacology evaluation
was requested.
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Patient with Very Low VMAX
Chart depicting this.
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BASIS OF APPARENT
FIRST-ORDER KINETICS
equations
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Pharmacokinetics
PRACTICE PROBLEMS AT END OF CHAPTER 2
WITH ANSWERS IN APPENDIX II
EQUATIONS DERIVED IN “PRINCIPLES OF
CLINICAL PHARMACOLOGY” TEXTBOOK