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
Background and ObjectivesThis 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.MethodsDuring 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 (Cmax) 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.ResultsFollowing administration, vonoprazan was rapidly absorbed (time to reach Cmax, 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 Cmax of vonoprazan, respectively, were observed following clarithromycin. In contrast, AUC and Cmax 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.ConclusionsModest 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.govNCT02774902.
Clinical Drug Investigation