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.

Abstract

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 40mg on days 1 and 8, and clarithromycin 1000mg 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, 2h), 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 7.2h on day 1 and 9.4h 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. CLINICALTRIALS.GOV: NCT02774902.