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Purpose <p>The interaction between proton pump inhibitors (PPIs) and clopidogrel in acute coronary syndrome (ACS) patients is mediated by CYP2C19 genetic variants. This study quantitatively assessed their CYP2C19 genotype-dependent impact on clopidogrel pharmacokinetics and pharmacodynamics using clinical data and physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) modeling.</p> Methods <p>A total of 409 ACS patients from a prospective clinical study were genotyped for <i>CYP2C19</i> (*1, 2, and 3 alleles) and evaluated for platelet reactivity index (PRI) following clopidogrel therapy, with or without concomitant pantoprazole or lansoprazole use. A PBPK model was developed in PK-Sim, incorporating <i>CYP2C19</i>-specific metabolic pathways, and linked with a pharmacodynamic model of P2Y12 receptor inhibition to simulate the effects of genotypes and PPIs on platelet inhibition.</p> Results <p>In extensive metabolizer individuals, PPI coadministration modestly increased platelet reactivity, while no significant change occurred in poor metabolizers. The PBPK simulations accurately predicted pharmacokinetic parameters, with over 90% of C<sub>max</sub> and AUC values within 0.5–twofold of clinical data. The integrated drug-drug-gene interaction–pharmacodynamic framework effectively captured the active metabolite’s exposure and platelet inhibition dynamics.</p> Conclusions <p>These results provide a quantitative understanding of the genotype- and PPI-dependent effects on clopidogrel’s pharmacodynamics, offering a tool to personalize therapy in ACS patients.</p>

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Integrating Clinical Evidence with PBPK Modeling to Assess PPI-Clopidogrel-CYP2C19 Interactions in Chinese ACS Patients

  • 期刊论文

  • 发表日期：

    2026年7月21日

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  • Ya-xin Liu,
  • Yun Kuang,
  • Jun-long Ma,
  • Jin-long Liu,
  • Nuo Xu,
  • Qi Pei,
  • Li-ying Gong,
  • Guo-ping Yang

摘要

Purpose

The interaction between proton pump inhibitors (PPIs) and clopidogrel in acute coronary syndrome (ACS) patients is mediated by CYP2C19 genetic variants. This study quantitatively assessed their CYP2C19 genotype-dependent impact on clopidogrel pharmacokinetics and pharmacodynamics using clinical data and physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) modeling.

Methods

A total of 409 ACS patients from a prospective clinical study were genotyped for CYP2C19 (*1, 2, and 3 alleles) and evaluated for platelet reactivity index (PRI) following clopidogrel therapy, with or without concomitant pantoprazole or lansoprazole use. A PBPK model was developed in PK-Sim, incorporating CYP2C19-specific metabolic pathways, and linked with a pharmacodynamic model of P2Y12 receptor inhibition to simulate the effects of genotypes and PPIs on platelet inhibition.

Results

In extensive metabolizer individuals, PPI coadministration modestly increased platelet reactivity, while no significant change occurred in poor metabolizers. The PBPK simulations accurately predicted pharmacokinetic parameters, with over 90% of Cmax and AUC values within 0.5–twofold of clinical data. The integrated drug-drug-gene interaction–pharmacodynamic framework effectively captured the active metabolite’s exposure and platelet inhibition dynamics.

Conclusions

These results provide a quantitative understanding of the genotype- and PPI-dependent effects on clopidogrel’s pharmacodynamics, offering a tool to personalize therapy in ACS patients.