title: Development of a physiology-directed population pharmacokinetic and pharmacodynamic model for characterizing the impact of genetic and demographic factors on clopidogrel response in healthy adults.
abstract: Clopidogrel (Plavix®), is a widely used antiplatelet agent, which shows high inter-individual variability in treatment response in patients following the standard dosing regimen. In this study, a physiology-directed population pharmacokinetic/pharmacodynamic (PK/PD) model was developed based on clopidogrel and clopidogrel active metabolite (clop-AM) data from the PAPI and the PGXB2B studies using a step-wise approach in NONMEM (version 7.2). The developed model characterized the in vivo disposition of clopidogrel, its bioactivation into clop-AM in the liver and subsequent platelet aggregation inhibition in the systemic circulation reasonably well. It further allowed the identification of covariates that significantly impact clopidogrel's dose-concentration-response relationship. In particular, CYP2C19 intermediate and poor metabolizers converted 26.2% and 39.5% less clopidogrel to clop-AM, respectively, compared to extensive metabolizers. In addition, CES1 G143E mutation carriers have a reduced CES1 activity (82.9%) compared to wild-type subjects, which results in a significant increase in clop-AM formation. An increase in BMI was found to significantly decrease clopidogrel's bioactivation, whereas increased age was associated with increased platelet reactivity. Our PK/PD model analysis suggests that, in order to optimize clopidogrel dosing on a patient-by-patient basis, all of these factors have to be considered simultaneously, e.g. by using quantitative clinical pharmacology tools.
authors.affiliation: Department of Pharmaceutics, Center for Pharmacometrics and Systems Pharmacology, University of Florida at Lake Nona, Orlando, FL, USA.
authors.forename: Xi-Ling
authors.initials: XL
authors.lastname: Jiang
authors.affiliation: Department of Pharmaceutics, Center for Pharmacometrics and Systems Pharmacology, University of Florida at Lake Nona, Orlando, FL, USA.
authors.forename: Snehal
authors.initials: S
authors.lastname: Samant
authors.affiliation: Division of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: Joshua P
authors.initials: JP
authors.lastname: Lewis
authors.affiliation: Division of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: Richard B
authors.initials: RB
authors.lastname: Horenstein
authors.affiliation: Division of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: Alan R
authors.initials: AR
authors.lastname: Shuldiner
authors.affiliation: Division of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: Laura M
authors.initials: LM
authors.lastname: Yerges-Armstrong
authors.affiliation: Mathematical Institute, Leiden University, PB 9512, 2300 RA Leiden, The Netherlands.
authors.forename: Lambertus A
authors.initials: LA
authors.lastname: Peletier
authors.affiliation: Department of Pharmaceutics, Center for Pharmacometrics and Systems Pharmacology, University of Florida at Lake Nona, Orlando, FL, USA.
authors.forename: Lawrence J
authors.initials: LJ
authors.lastname: Lesko
authors.affiliation: Department of Pharmaceutics, Center for Pharmacometrics and Systems Pharmacology, University of Florida at Lake Nona, Orlando, FL, USA. Electronic address: sschmidt@cop.ufl.edu.
authors.forename: Stephan
authors.initials: S
authors.lastname: Schmidt
mesh_terms: D000328:Adult; D000077144:Clopidogrel; D003710:Demography; D005260:Female; D005838:Genotype; D006801:Humans; D008099:Liver / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D010975:Platelet Aggregation Inhibitors; D000077144:Clopidogrel; D013988:Ticlopidine
keywords: CES1; CYP2C19; Clopidogrel; PK/PD modeling; Pharmacogenetics; Physiology-directed population pharmacokinetic and pharmacodynamic model