In Vitro Assessment of Potential for CYP-Inhibition-Based Drug–Drug Interaction Between Vonoprazan and Clopidogrel
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.
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.
All studies were performed according to the applicable institutional guidelines.
All studies reported here were supported and conducted by Takeda Pharmaceutical Company Limited.
- 2.Murakami K, Sakurai Y, Shiino M, Funao N, Nishimura A, Asaka M. Vonoprazan, a novel potassium-competitive acid blocker, as a component of first-line and second-line triple therapy for Helicobacter pylori eradication: a phase III, randomised, double-blind study. Gut. 2016;65:1439–46.CrossRefGoogle Scholar
- 3.Shin JM, Inatomi N, Munson K, Strugatsky D, Tokhtaeva E, Vagin O, Sachs G. Characterization of a novel potassium-competitive acid blocker of the gastric H, K-ATPase, 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine monofumarate (TAK-438). J Pharmacol Exp Ther. 2011;339(2):412–20.Google Scholar
- 5.Jenkins H, Sakurai Y, Nishimura A, Okamoto H, Hibberd M, Jenkins R, Yoneyama T, Ashida K, Ogama Y, Warrington S. Randomised clinical trial: safety, tolerability, pharmacokinetics and pharmacodynamics of repeated doses of TAK-438 (vonoprazan), a novel potassium-competitive acid blocker, in healthy male subjects. Aliment Pharmacol Ther. 2015;41:636–48.CrossRefGoogle Scholar
- 6.Sakurai Y, Mori Y, Okamoto H, Nishimura A, Komura E, Araki T, Shiramoto M. Acid-inhibitory effects of vonoprazan 20 mg compared with esomeprazole 20 mg or rabeprazole 10 mg in healthy adult male subjects—a randomised open-label cross-over study. Aliment Pharmacol Ther. 2015;42:719–30.CrossRefGoogle Scholar
- 10.Sakurai Y, Nishimura A, Kennedy G, Hibberd M, Jenkins R, Okamoto H, Yoneyama T, Jenkins H, Ashida K, Irie S, Täubel J. Safety, tolerability, pharmacokinetics, and pharmacodynamics of single rising TAK-438 (vonoprazan) doses in healthy male Japanese/non-Japanese subjects. Clin Transl Gastroenterol. 2015;6:e94.CrossRefGoogle Scholar
- 11.Kagami T, Yamade M, Suzuki T, Uotani T, Hamaya Y, Iwaizumi M, Osawa S, Sugimoto K, Umemura K, Miyajima H, Furuta T. Comparative study of effects of vonoprazan and esomeprazole on antiplatelet function of clopidogrel or prasugrel in relation to CYP2C19 genotype. Clin Pharmacol Ther. 2018;103(5):906–13.CrossRefGoogle Scholar
- 15.Grimm SW, Einolf HJ, Hall SD, He K, Lim HK, Ling KHJ, Lu C, Nomeir AA, Seibert E, Skordos KW, Tonn GR, Van Horn R, Wang RW, Wong YN, Yang TJ, Obach RS. The conduct of in vitro studies to address time-dependent inhibition of drug-metabolizing enzymes: a perspective of the pharmaceutical research and manufacturers of America. Drug Metab Dispos. 2009;37(7):1355–70.CrossRefGoogle Scholar
- 16.US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER). Draft guidance for Industry. In vitro metabolism- and transporter-mediated drug–drug interaction studies. Silver Spring, MD: FDA; 2017. https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM581965.pdf. Accessed 15 Sep 2018.
- 17.European Medicines Agency. Guideline on the investigation of drug interactions. London: EMA; 2013. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/07/WC500129606.pdf. Accessed 15 Sep 2018.
- 18.Ministry of Health, Labour and Welfare, Japan. Guideline of drug interaction studies for drug development and appropriate provision of information. Tokyo, Japan: Ministry of Health; 2018. https://www.pmda.go.jp/files/000225191.pdf. Accessed 15 Sep 2018.
- 24.Hardman JG, Limbird LE, Gilman AG. Goodman & Gilman’s The pharmacological basis of therapeutics. 10th ed. New York: McGraw-Hill; 2001. p. 2013.Google Scholar
- 30.Shaw SA, Balasubramanian B, Bonacorsi S, Cortes JC, Cao K, Chen BC, Dai J, Decicco C, Goswami A, Guo Z, Hanson R, Humphreys WG, Lam PYS, Li W, Mathur A, Maxwell BD, Michaudel Q, Peng L, Pudzianowski A, Qiu F, Su S, Sun D, Tymiak AA, Vokits BP, Wang B, Wexler R, Wu DR, Zhang Y, Zhao R, Baran PS. Synthesis of biologically active piperidine metabolites of clopidogrel: determination of structure and analyte development. J Org Chem. 2015;80:7019–32.CrossRefGoogle Scholar
- 31.Kazui M, Nishiya Y, Ishizuka T, Hagihara K, Farid NA, Okazaki O, Ikeda T, Kurihara A. Identification of the human cytochrome P450 enzymes involved in the two oxidative steps in the bioactivation of clopidogrel to its pharmacologically active metabolite. Drug Metab Dispos. 2010;38(1):92–9.CrossRefGoogle Scholar
- 32.Hagihara K, Kazui M, Kurihara A, Yoshiike M, Honda K, Okazaki O, Farid NA, Ikeda T. A possible mechanism for the differences in efficiency and variability of active metabolite formation from thienopyridine antiplatelet agents, prasugrel and clopidogrel. Drug Metab Dispos. 2009;37(11):2145–52.CrossRefGoogle Scholar
- 33.Liu C, Chen Z, Zhong K, Li L, Zhu W, Chen X, Zhong D. Human liver cytochrome P450 enzymes and microsomal thiol methyltransferase are involved in the stereoselective formation and methylation of the pharmacologically active metabolite of clopidogrel. Drug Metab Dispos. 2015;43:1632–41.CrossRefGoogle Scholar
- 40.Suzuki A, Iida I, Hirota M, Akimoto M, Higuchi S, Suwa T, Tani M, Ishizaki T, Chiba K. CYP isoforms involved in the metabolism of clarithromycin in vitro: comparison between the identification from disappearance rate and that from formation rate of metabolites. Drug Metab Pharmacokin. 2003;18(2):104–13.CrossRefGoogle Scholar