Pharmacokinetics and Safety of Triple Therapy with Vonoprazan,Amoxicillin, and Clarithromycin or Metronidazole: A Phase 1, Open-Label,Randomized, Crossover Study

Introduction

Vonoprazan (TAK-438) is a novel potassium-competitive acid blocker that inhibits gastric H⁺, K⁺-ATPase. The objectives of this study were to evaluate the influence of triple therapy with vonoprazan–amoxicillin–clarithromycin or vonoprazan–amoxicillin–metronidazole on the pharmacokinetics of each component of the triple therapies (primary) and to evaluate the safety and tolerability of vonoprazan-based triple therapies (secondary) in healthy adults.

Methods

In this single-center, phase 1, open-label, randomized, four-way crossover study, Helicobacter pylori-negative, healthy Japanese male subjects were randomly assigned to 1 of 4 treatment sequences in two cohorts (12 subjects per cohort). Each treatment sequence comprised four treatment periods separated by a washout period of 7 or 14 days. Pharmacokinetic parameters for vonoprazan, amoxicillin, clarithromycin and metronidazole in single therapy or triple therapies were assessed. All adverse events were recorded.

Results

Compared with single therapy, triple therapy with vonoprazan–amoxicillin–clarithromycin increased the area under the plasma concentration–time curve from time 0–12 h (AUC_0-12) and maximum plasma concentration (C _max) of plasma vonoprazan free base by 1.846- and 1.868-fold, respectively, and increased the AUC_0-12 and C _max of plasma clarithromycin by 1.450- and 1.635-fold, respectively. Triple therapy with vonoprazan–amoxicillin–metronidazole had no influence on the pharmacokinetics of vonoprazan or metronidazole. The pharmacokinetics of amoxicillin was not influenced by vonoprazan-based triple therapies. Seven adverse events were reported. Two subjects discontinued because of an adverse event (rash, liver function test abnormal); both events were considered to be study drug-related.

Conclusion

In healthy Japanese male subjects, triple therapy with vonoprazan–amoxicillin–clarithromycin increased vonoprazan and clarithromycin exposure. The safety and tolerability profile of triple therapy with vonoprazan–amoxicillin–clarithromycin or vonoprazan–amoxicillin–metronidazole was favorable in this population.

Funding

Takeda Pharmaceutical Company Ltd.

Trial registration

JapicCTI-153102.