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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

Abstract

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.

Methods

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.

Results

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.

Conclusions

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.

Notes

Acknowledgements

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.

Funding

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

References

  1. 1.
    Ashida K, Sakurai Y, Hori T, Kudou K, Nishimura A, Hiramatsu N, Umegaki E, Iwakiri K. Randomised clinical trial: vonoprazan, a novel potassium-competitive acid blocker, vs. lansoprazole for the healing of erosive oesophagitis. Aliment Pharmacol Ther. 2016;43:240–51.CrossRefGoogle Scholar
  2. 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. 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
  4. 4.
    Martinucci I, Blandizzi C, Bodini G, Marabotto E, Savarino V, Marchi S, de Bortoli N, Savarino E. Vonoprazan fumarate for the management of acid-related diseases. Expert Opin Pharmacother. 2017;18(11):1145–52.CrossRefGoogle Scholar
  5. 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. 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
  7. 7.
    Kogame A, Takeuchi T, Nonaka M, Yamasaki H, Kawaguchi N, Bernards A, Tagawa Y, Morohashi A, Kondo T, Moriwaki T, Asahi S. Disposition and metabolism of TAK-438 (vonoprazan fumarate), a novel potassium-competitive acid blocker, in rats and dogs. Xenobiotica. 2017;47(3):255–66.CrossRefGoogle Scholar
  8. 8.
    Yamasaki H, Kawaguchi N, Nonaka M, Takahashi J, Morohashi A, Hirabayashi H, Moriwaki T, Asahi S. In vitro metabolism of TAK-438, vonoprazan fumarate, a novel potassium-competitive acid blocker. Xenobiotica. 2017;47(12):1027–34.CrossRefGoogle Scholar
  9. 9.
    Yoneyama T, Teshima K, Jinno F, Kondo T, Asahi S. A validated simultaneous quantification method for vonoprazan (TAK-438F) and its 4 metabolites in human plasma by the liquid chromatography-tandem mass spectrometry. J Chromatogr B. 2016;1015:42–9.CrossRefGoogle Scholar
  10. 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. 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
  12. 12.
    Nishihara M, Czerniak R. CYP-mediated drug–drug interaction is not a major determinant of attenuation of anti-platelet function of clopidogrel by vonoprazan. Clin Pharmacol Ther. 2018;104(1):31–2.CrossRefGoogle Scholar
  13. 13.
    Obach RS, Walsky RL, Venkatakrishnan K. Mechanism-based inactivation of human cytochrome P450 enzymes and the prediction of drug–drug interactions. Drug Metab Dispos. 2007;35(2):246–55.CrossRefGoogle Scholar
  14. 14.
    Zvyaga T, Chang SY, Chen C, Yang Z, Vuppugalla R, Hurley J, Thorndike D, Wagner A, Chimalakonda A, Rodrigues AD. Evaluation of six proton pump inhibitors as inhibitors of various human cytochrome P450: focus on cytochrome P450 2C19. Drug Metab Dispos. 2012;40(9):1698–711.CrossRefGoogle Scholar
  15. 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. 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. 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. 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.
  19. 19.
    Shirasaka Y, Sager JE, Lutz JD, Davis C, Isoherranen N. Inhibition of CYP2C19 and CYP3A4 by omeprazole metabolites and their contribution to drug–drug interactions. Drug Metab Dispos. 2013;41(7):1414–24.CrossRefGoogle Scholar
  20. 20.
    Yang J, Liao M, Shou M, Jamei M, Yeo KR, Tucker GT, Rostami-Hodjegan A. Cytochrome p450 turnover: regulation of synthesis and degradation, methods for determining rates, and implications for the prediction of drug interactions. Curr Drug Metab. 2008;9:384–93.CrossRefGoogle Scholar
  21. 21.
    Lu WJ, Huang JD, Lai ML. The effects of ergoloid mesylates and ginkgo biloba on the pharmacokinetics of ticlopidine. J Clin Pharmacol. 2006;46:628–34.CrossRefGoogle Scholar
  22. 22.
    Andersson T, Hassan-Alin M, Hasselgren G, Röhss K, Weidolf L. Pharmacokinetic studies with esomeprazole, the (S)-isomer of omeprazole. Clin Pharmacokinet. 2001;40(6):411–26.CrossRefGoogle Scholar
  23. 23.
    Maeda K, Takano J, Ikeda Y, Fujita T, Oyama Y, Nozawa K, Kumagai Y, Sugiyama Y. Nonlinear pharmacokinetics of oral quinidine and verapamil in healthy subjects: a clinical microdosing study. Clin Pharmacol Ther. 2011;90(2):263–70.CrossRefGoogle Scholar
  24. 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
  25. 25.
    Xu L, Chen Y, Pan Y, Skiles GL, Shou M. Prediction of human drug–drug interactions from time-dependent inactivation of CYP3A4 in primary hepatocytes using a population-based simulator. Drug Metab Dispos. 2009;37(12):2330–9.CrossRefGoogle Scholar
  26. 26.
    Dansette PM, Levent D, Hessani A, Mansuy D. Bioactivation of clopidogrel and prasugrel: factors determining the stereochemistry of the thiol metabolite double bond. Chem Res Toxicol. 2015;28(6):1338–45.CrossRefGoogle Scholar
  27. 27.
    Zhang H, Lau WC, Hollenberg PF. Formation of the thiol conjugates and active metabolite of clopidogrel by human liver microsomes. Mol Pharmacol. 2012;82(2):302–9.CrossRefGoogle Scholar
  28. 28.
    Tuffal G, Roy S, Lavisse M, Brasseur D, Schofield J, Touchard ND, Savi P, Bremond N, Rouchon MC, Hurbin F, Sultan E. An improved method for specific and quantitative determination of the clopidogrel active metabolite isomers in human plasma. Thromb Haemost. 2011;105:696–705.CrossRefGoogle Scholar
  29. 29.
    Takahashi M, Pang H, Kawabata K, Farid NA, Kurihara A. Quantitative determination of clopidogrel active metabolite in human plasma by LC-MS/MS. J Pharm Biomed Anal. 2008;48:1219–24.CrossRefGoogle Scholar
  30. 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. 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. 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. 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
  34. 34.
    Burt HJ, Galetin A, Houston JB. IC50-based approaches as an alternative method for assessment of time-dependent inhibition of CYP3A4. Xenobiotica. 2010;40(5):331–43.CrossRefGoogle Scholar
  35. 35.
    Turpeinen M, Tolonen A, Uusitalo J, Jalonen J, Pelkonen O, Laine K. Effect of clopidogrel and ticlopidine on cytochrome P450 2B6 activity as measured by bupropion hydroxylation. Clin Pharmacol Ther. 2005;77:553–9.CrossRefGoogle Scholar
  36. 36.
    Andersson T, Hassan-Alin M, Hasselgren G, Röhss K. Drug interaction studies with esomeprazole, the (S)-isomer of omeprazole. Clin Pharmacokinet. 2001;40(7):523–37.CrossRefGoogle Scholar
  37. 37.
    Backman JT, Olkkola KT, Aranko K, Himberg JJ, Neuvonen PJ. Dose of midazolam should be reduced during diltiazem and verapamil treatments. Br J Clin Pharmacol. 1994;37:221–5.CrossRefGoogle Scholar
  38. 38.
    Sakurai Y, Shiino M, Okamoto H, Nishimura A, Nakamura K, Hasegawa S. Pharmacokinetics and safety of triple therapy with vonoprazan, amoxicillin, and clarithromycin or metronidazole: a phase 1, open-label, randomized, crossover study. Adv Ther. 2016;33:1519–35.CrossRefGoogle Scholar
  39. 39.
    Niwa T, Morimoto M, Hirai T, Hata T, Hayashi M, Imagawa Y. Effects of penicillin-based antibiotics, amoxicillin, ampicillin, and piperacillin, on drug-metabolizing activities of human hepatic cytochromes P450. J Toxicol Sci. 2016;41(1):143–6.CrossRefGoogle Scholar
  40. 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

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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