Abstract
Background and Objectives
This phase I, open-label, sequential design study assessed the effect of multiple oral doses of the potent cytochrome P450 (CYP) 3A4 inhibitor clarithromycin on the pharmacokinetics of a single oral dose of vonoprazan.
Methods
During the 10-day treatment period, 16 healthy male subjects received vonoprazan 40 mg on days 1 and 8, and clarithromycin 1000 mg on days 3–9, with the pharmacokinetics of both examined. Primary endpoints included the maximum observed plasma concentration (C max) and area under the plasma concentration–time curve (AUC) of vonoprazan and its major metabolites (M-I, M-II, M-III, and M-IV-Sul). Safety was also assessed.
Results
Following administration, vonoprazan was rapidly absorbed (time to reach C max, 2 h), consistent with its known pharmacokinetic profile. This was unchanged in the presence of clarithromycin. Plasma concentrations declined thereafter, with a mean apparent terminal elimination half-life of 7.2 h on day 1 and 9.4 h on day 8. Small-to-moderate increases (1.6- and 1.4-fold) in mean AUC and C max of vonoprazan, respectively, were observed following clarithromycin. In contrast, AUC and C max for vonoprazan metabolites decreased, except for M-IV-Sul, which increased approximately 2.1- and 1.5-fold, respectively. Overall, vonoprazan was well tolerated, with mild or moderate treatment-emergent adverse events occurring in six (37.5%) subjects receiving either vonoprazan and/or clarithromycin.
Conclusions
Modest increases in plasma concentrations of the potent CYP3A4 inhibitor clarithromycin and vonoprazan were observed during coadministration, however these differences were not considered clinically significant. Vonoprazan had a favorable safety and tolerability profile, and no serious adverse events were reported.
ClinicalTrials.gov
NCT02774902.
References
Kagami T, Sahara S, Ichikawa H, et al. Potent acid inhibition by vonoprazan in comparison with esomeprazole with reference to CYP2C19 genotype. Aliment Pharmacol Ther. 2016;43:1048–59.
Shin JM, Inatomi N, Munson K, et al. 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-methylmethanamin e monofumarate (TAK-438). J Pharmacol Exp Ther. 2011;339:412–20.
Sakurai Y, Nishimura A, Kennedy G, et al. 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.
Jenkins H, Sakurai Y, Nishimura A, et al. 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.
Zhao F, Wang J, Yang Y, et al. Effect of CYP2C19 genetic polymorphisms on the efficacy of proton pump inhibitor-based triple therapy for Helicobacter pylori eradication: a meta-analysis. Helicobacter. 2008;13:532–41.
Klotz U, Schwab M, Treiber G. CYP2C19 polymorphism and proton pump inhibitors. Basic Clin Pharmacol Toxicol. 2004;95:2–8.
Echizen H. The first-in-class potassium-competitive acid blocker, vonoprazan fumarate: pharmacokinetic and pharmacodynamic considerations. Clin Pharmacokinet. 2016;55:409–18.
Sakurai Y, Shiino M, Okamoto H, et al. 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.
Meibohm B, Beierle I, Derendorf H. How important are gender differences in pharmacokinetics? Clin Pharmacokinet. 2002;41:329–42.
Acknowledgements
The authors wish to acknowledge Dr. Nicolas Fauchoux, the Principal Investigator, who was responsible for the conduct of the study, as well as the clinic staff.
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Ethical approval
This study was conducted in accordance with the Declaration of Helsinki and International Conference of Harmonization—Good Clinical Practice, and all applicable local laws and regulations, between August and September 2010 at the Biotrial study site (Clinical Pharmacology Unit), Rennes, France. The study was authorized by the French Medicine Agency and approved by the Investigational Review Board, the Comité de Protection des Personnes—Ouest VI (Brest, France). All subjects provided written informed consent prior to the initiation of study procedures.
Funding
This study was funded in full by Takeda Pharmaceutical Company Limited. Medical writing assistance was provided by Jordana Campbell, BSc, and Tania Dickson, PhD, of ProScribe—part of the Envision Pharma Group, and was funded by Takeda Pharmaceutical Company Limited. ProScribe’s services complied with international guidelines for Good Publication Practice (GPP3).
Conflicts of interest
Helen Jenkins and Richard Jenkins are employees of Takeda Pharmaceutical Company. Alain Patat is employed by Biotrial, who conducted the study on behalf of Takeda Pharmaceutical Company. All authors contributed to the study design, data analysis, writing, and critical review of the manuscript. Takeda Pharmaceutical Company Limited was involved in the study design, data collection, data analysis, and preparation of the manuscript.
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Jenkins, H., Jenkins, R. & Patat, A. Effect of Multiple Oral Doses of the Potent CYP3A4 Inhibitor Clarithromycin on the Pharmacokinetics of a Single Oral Dose of Vonoprazan: A Phase I, Open-Label, Sequential Design Study. Clin Drug Investig 37, 311–316 (2017). https://doi.org/10.1007/s40261-016-0488-6
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DOI: https://doi.org/10.1007/s40261-016-0488-6