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
- 409 Downloads
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.
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.
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.
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.
KeywordsClarithromycin Single Oral Dose Gastric Acid Secretion Multiple Oral Dose Potent CYP3A4 Inhibitor
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.
Compliance with Ethical Standards
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.
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.
- 2.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.CrossRefPubMedPubMedCentralGoogle Scholar
- 4.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.CrossRefPubMedPubMedCentralGoogle Scholar