In Vitro Assessment of Potential for CYP-Inhibition-Based Drug–Drug Interaction Between Vonoprazan and Clopidogrel

  • Mitsuhiro NishiharaEmail author
  • Hitomi Yamasaki
  • Richard Czerniak
  • Helen Jenkins
Original Research Article


Background and Objectives

It was recently proposed that CYP-mediated drug–drug interactions (DDIs) of vonoprazan with clopidogrel and prasugrel can attenuate the antiplatelet actions of the latter two drugs. Clopidogrel is metabolized to the pharmacologically active metabolite H4 and its isomers by multiple CYPs, including CYP2C19 and CYP3A4. Therefore, to investigate the possibility of CYP-based DDIs, in vitro metabolic inhibition studies using CYP probe substrates or radiolabeled clopidogrel and human liver microsomes (HLMs) were conducted in this work.


Reversible inhibition studies focusing on the effects of vonoprazan on CYP marker activities and the formation of the [14C]clopidogrel metabolite H4 were conducted with and without pre-incubation using HLMs. Time-dependent inhibition (TDI) kinetics were also measured.


It was found that vonoprazan is not a significant direct inhibitor of any CYP isoforms (IC50 ≥ 16 μM), but shows the potential for TDI of CYP2B6, CYP2C19, and CYP3A4/5. This TDI was weaker than the inhibition induced by the corresponding reference inhibitors ticlopidine, esomeprazole, and verapamil, based on the measured potencies (kinact/KI ratio and the R2 value). In a more direct in vitro experiment, vonoprazan levels of up to 10 µM (a 100-fold higher concentration than the plasma Cmax of 75.9 nM after taking 20 mg once daily for 7 days) did not suppress the formation of the active metabolite H4 or other oxidative metabolites of [14C]clopidogrel in a reversible or time-dependent manner. Additionally, an assessment of clinical trials and post-marketing data suggested no evidence of a DDI between vonoprazan and clopidogrel.


The body of evidence shows that the pharmacodynamic DDI reported between vonoprazan and clopidogrel is unlikely to be caused by the inhibition of CYP2B6, CYP2C19, or CYP3A4/5 by vonoprazan.



The authors would like to thank Suresh K. Balani of Global Drug Metabolism and Pharmacokinetics, the Global Vonoprazan Project Team members at Takeda, Hideki Hirabayashi of Drug Metabolism and Pharmacokinetics Research Laboratories, and Junzo Takahashi for their contributions to these studies.

Author contributions

MN and HY mainly wrote the manuscript. MN, HY, RC and HJ designed the research and analyzed the data. HY performed the research.

Compliance with Ethical Standards

Conflict of interest

All the authors are employees of or have retired from working for Takeda Pharmaceutical Company Limited. The draft manuscript was prepared by Axcelead. The authors declare no other conflicts of interest.

Ethical approval

All studies were performed according to the applicable institutional guidelines.


All studies reported here were supported and conducted by Takeda Pharmaceutical Company Limited.


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Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  1. 1.Global Drug Metabolism and Pharmacokinetics, Takeda Pharmaceuticals International Co.CambridgeUSA
  2. 2.Drug Disposition and Analysis, Research DivisionAxcelead Drug Discovery Partners, Inc.FujisawaJapan
  3. 3.Quantitative Clinical PharmacologyTakeda Pharmaceuticals International Co.CambridgeUSA
  4. 4.d3 Medicine, A Certara CompanyLondonUK

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