Population pharmacokinetic‐pharmacodynamic modeling of clopidogrel for dose regimen optimization based on CYP2C19 phenotypes: A proof of concept study

Abstract

Clopidogrel is an antiplatelet drug used to reduce the risk of acute coronary syndrome and stroke. It is converted by CYP2C19 to its active metabolite; therefore, poor metabolizers (PMs) of CYP2C19 exhibit diminished antiplatelet effects. Herein, we conducted a proof‐of‐concept study for using population pharmacokinetic‐pharmacodynamic (PK‐PD) modeling to recommend a personalized clopidogrel dosing regimen for individuals with varying CYP2C19 phenotypes and baseline P2Y12 reaction unit (PRU) levels. Data from a prospective phase I clinical trial involving 36 healthy male participants were used to develop the population PK‐PD model predicting the concentrations of clopidogrel, clopidogrel H4, and clopidogrel carboxylic acid, and linking clopidogrel H4 concentrations to changes in PRU levels. A two‐compartment model effectively described the PKs of both clopidogrel and clopidogrel carboxylic acid, and a one‐compartment model of those of clopidogrel H4. The CYP2C19 phenotype was identified as a significant covariate influencing the metabolic conversion of the parent drug to its metabolites. A PD submodel of clopidogrel H4 that stimulated the fractional turnover rate of PRU levels showed the best performance. Monte Carlo simulations suggested that PMs require three to four times higher doses than extensive metabolizers to reach the target PRU level. Individuals within the top 20th percentile of baseline PRU levels were shown to require 2.5–3 times higher doses than those in the bottom 20th percentile. We successfully developed a population PK‐PD model for clopidogrel considering the impact of CYP2C19 phenotypes and baseline PRU levels. Further studies are necessary to confirm actual dosing recommendations for clopidogrel.

Integrating Clopidogrel’s First-Pass Effect in a Joint Semi-Physiological Population Pharmacokinetic Model of the Drug and Its Inactive Carboxylic Acid Metabolite

“…It was presumed that all parent drugs would ultimately undergo metabolism in this compartment. Integrated semi-physiological models of similar structure with FPEs have been previously published [4,24,36,37]. The model employed a physiological liver volume of 1.5 L and a liver plasma flow (Q h ) of 50 L/h [24].…”

“…Certain parameters needed to be fixed to ensure the stability of the model. Hence, F aM was fixed to the estimated value of 12%, which corresponded to the literature data [1][2][3][4]. Nevertheless, a sensitivity analysis was performed by varying the values of F aM at 10% and 15%.…”

“…Most of the absorbed CLO (approximately 85% of an oral dose) is hydrolyzed by esterase to the inactive metabolite clopidogrel carboxylic acid (CLO-CA). Approximately 10-15% of orally absorbed CLO is oxidized in two steps by cytochrome P450 (CYP) isoenzymes to its active metabolite clopidogrel thiol (CLO-TH) [1][2][3][4]. In the first oxidation step, which Pharmaceutics 2024, 16, 685 2 of 13 is catalyzed by CYP1A2, CYP2B6 and CYP2C19, an intermediate metabolite, 2-oxo-CLO, is formed.…”

“…To the best of our knowledge, there are only a few published population pharmacokinetic models describing CLO and its metabolites [4,[19][20][21][22][23][24], most of which focus on the CLO-TH metabolite in combination with the parent drug [4,[22][23][24] or alone [21]. Physiologically based pharmacokinetic models have also been developed [3,[25][26][27].…”

“…Although the metabolite CLO-CA is inactive, its predominant (compared to its parent drug and metabolites) presence in plasma underscores the importance of characterizing its formation and pharmacokinetic profile. To date, this inactive metabolite's population pharmacokinetics models have been investigated in only a few publications, including a single jointpopulation pharmacokinetic model with its parent drug [4,19,20]. Hence, the aim of this study was to synthesize data from two bioequivalence studies in order to characterize the process of the absorption of CLO and its conversion to CLO-CA through a joint population semi-physiological pharmacokinetic model.…”