Population pharmacokinetic analysis of clopidogrel in healthy Jordanian subjects with emphasis optimal sampling strategy

ABSTRACT Aim: Clopidogrel is metabolized primarily into an inactive carboxyl metabolite (clopidogrel‐IM) or to a lesser extent an active thiol metabolite. A population pharmacokinetic (PK) model was developed using NONMEM® to describe the time course of clopidogrel‐IM in plasma and to design a spars...

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Bibliographic Details
Published in:Biopharmaceutics & drug disposition 2013-05, Vol.34 (4), p.215-226
Main Authors: Yousef, A. M., Melhem, M., Xue, B., Arafat, T., Reynolds, D. K., Van Wart, S. A.
Format: Article
Language:English
Subjects:
Administration, Oral
Adolescent
Adult
Area Under Curve
Biological and medical sciences
Chromatography, High Pressure Liquid
Chromatography, Reverse-Phase
clopidogrel
clopidogrel carboxylic acid metabolite
enterohepatic recycling
Humans
Jordan
Male
Medical sciences
Middle Aged
Models, Biological
optimal sampling
Pharmacology. Drug treatments
Platelet Aggregation Inhibitors - pharmacokinetics
population pharmacokinetics
Ticlopidine - analogs & derivatives
Ticlopidine - pharmacokinetics
Time Factors
Young Adult
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Summary:ABSTRACT Aim: Clopidogrel is metabolized primarily into an inactive carboxyl metabolite (clopidogrel‐IM) or to a lesser extent an active thiol metabolite. A population pharmacokinetic (PK) model was developed using NONMEM® to describe the time course of clopidogrel‐IM in plasma and to design a sparse‐sampling strategy to predict clopidogrel‐IM exposures for use in characterizing anti‐platelet activity.Methods: Serial blood samples from 76 healthy Jordanian subjects administered a single 75 mg oral dose of clopidogrel were collected and assayed for clopidogrel‐IM using reverse phase high performance liquid chromatography. A two‐compartment (2‐CMT) PK model with first‐order absorption and elimination plus an absorption lag‐time was evaluated, as well as a variation of this model designed to mimic enterohepatic recycling (EHC). Optimal PK sampling strategies (OSS) were determined using WinPOPT based upon collection of 3–12 post‐dose samples.Results: A two‐compartment model with EHC provided the best fit and reduced bias in Cmax (median prediction error (PE%) of 9.58% versus 12.2%) relative to the basic two‐compartment model, AUC0‐24 was similar for both models (median PE% = 1.39%). The OSS for fitting the two‐compartment model with EHC required the collection of seven samples (0.25, 1, 2, 4, 5, 6 and 12 h). Reasonably unbiased and precise exposures were obtained when re‐fitting this model to a reduced dataset considering only these sampling times.Conclusions: A two‐compartment model considering EHC best characterized the time course of clopidogrel‐IM in plasma. Use of the suggested OSS will allow for the collection of fewer PK samples when assessing clopidogrel‐IM exposures. Copyright © 2013 John Wiley & Sons, Ltd.
ISSN:0142-2782
1099-081X
DOI:10.1002/bdd.1839