Drug-Drug Interaction by CYP Metabolism Is Not a Major Determinant of Attenuation of Anti-platelet Function of Clopidogrel by Coadministration with Vonoprazan

Abstract

Background

In a recent article, Kagami et al. reported that vonoprazan was an inhibitor of not only CYP3A4 but also CYP2C19, and that the CYP-mediated drug-drug interaction (DDI) between vonoprazan and clopidogrel or prasugrel attenuated their anti-platelet function [1]. Clopidogrel is pharmacologically activated to metabolite H4 and its isomers by multiple CYPs including CYP2C19 and CYP3A4 [2]. To investigate the report, in vitro metabolism studies were conducted using each CYP probe substrate or radiolabeled clopidogrel and human liver microsomes (HLM).

Methods

Inhibitory effects of vonoprazan on CYP marker activities and the formation of [¹⁴C]clopidogrel metabolite, H4 were evaluated with and without pre-incubation using HLM. In addition, kinetic studies were conducted for the evaluation of time-dependent inhibition (TDI).

Results

Vonoprazan showed no significant direct inhibition for any CYP isoforms (IC50 ≥ 16 µmol/L), but TDI for CYP2B6, CYP2C19 and CYP3A4. However, the inhibitory effects were much weaker than the corresponding compounds (ticlopidine, esomeprazole and verapamil, respectively) based on the measured k_inact/K_I ratios. In a more direct experiment, quantification of the metabolites of [¹⁴C]clopidogrel showed vonoprazan had no significant inhibitory effect on the formation of H4 and its isomers with and without pre-incubation at up to 10 µmol/L. Since vonoprazan does not inhibit the H4 formation even at 100-fold higher concentration than plasma C_max (35 nmol/L at a dose of 10 mg once daily for 7 days [3]), the inhibitory effect on the metabolism of clopidogrel is anticipated to be limited at the clinical dose. In our clinical studies, the pharmacokinetics of vonoprazan was not affected by CYP2C19 polymorphism. The triple therapy with vonoprazan-amoxicillin-clarithromycin showed no clinically significant mutual pharmacokinetic interactions between clarithromycin, a substrate and inhibitor of CYP3A4, and vonoprazan, and an increase in exposure of hydroxyclarithromycin, a metabolite of clarithromycin formed by CYP3A4 [4], which suggest that vonoprazan is not a CYP3A4 inhibitor in vivo. Additionally, the assessment of clinical trials and post-marketing data suggested no evidence of DDI between vonoprazan and clopidogrel or prasugrel ("data on file").

Conclusion

This observed pharmacodynamic drug interaction of clopidogrel is highly unlikely due to CYP3A4 or CYP2C19 inhibition by vonoprazan.