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Adv Ther. 2016 Sep;33(9):1519-35. doi: 10.1007/s12325-016-0374-x. Epub 2016 Jul 18.

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

Author information

1
Clinical Science, Takeda Development Center Japan, Takeda Pharmaceutical Company Limited, Osaka, Japan. yuuichi.sakurai@takeda.com.
2
Clinical Science, Takeda Development Center Japan, Takeda Pharmaceutical Company Limited, Osaka, Japan.
3
Medical Writing Department, Takeda Development Center Japan, Takeda Pharmaceutical Company Limited, Osaka, Japan.
4
Clinical Pharmacology Department, Takeda Development Center Japan, Takeda Pharmaceutical Company Limited, Osaka, Japan.
5
CVM Marketing, Japan Pharma Business Unit, Takeda Pharmaceutical Company Limited, Tokyo, Japan.
6
Medical Corporation Houeikai, Sekino Clinical Pharmacology Clinic, Tokyo, Japan.
7
Pharmaspur Inc., Tokyo, Japan.

Abstract

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 (AUC0-12) and maximum plasma concentration (C max) of plasma vonoprazan free base by 1.846- and 1.868-fold, respectively, and increased the AUC0-12 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.

KEYWORDS:

Drug interactions; Gastroenterology; Helicobacter pylori; Pharmacokinetics; Potassium-competitive acid blocker; Safety; TAK-438; Triple therapy; Vonoprazan

PMID:
27432383
DOI:
10.1007/s12325-016-0374-x
[Indexed for MEDLINE]

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