title: Pharmacokinetics and Safety of Triple Therapy with Vonoprazan, Amoxicillin, and Clarithromycin or Metronidazole: A Phase 1, Open-Label, Randomized, Crossover Study.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  Takeda Pharmaceutical Company Ltd.
  
  
  
  JapicCTI-153102.
authors.affiliation: Clinical Science, Takeda Development Center Japan, Takeda Pharmaceutical Company Limited, Osaka, Japan. yuuichi.sakurai@takeda.com.
authors.forename: Yuuichi
authors.initials: Y
authors.lastname: Sakurai
authors.affiliation: Clinical Science, Takeda Development Center Japan, Takeda Pharmaceutical Company Limited, Osaka, Japan.|Medical Writing Department, Takeda Development Center Japan, Takeda Pharmaceutical Company Limited, Osaka, Japan.
authors.forename: Madoka
authors.initials: M
authors.lastname: Shiino
authors.affiliation: Clinical Pharmacology Department, Takeda Development Center Japan, Takeda Pharmaceutical Company Limited, Osaka, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Okamoto
authors.affiliation: Clinical Science, Takeda Development Center Japan, Takeda Pharmaceutical Company Limited, Osaka, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Nishimura
authors.affiliation: Clinical Science, Takeda Development Center Japan, Takeda Pharmaceutical Company Limited, Osaka, Japan.|CVM Marketing, Japan Pharma Business Unit, Takeda Pharmaceutical Company Limited, Tokyo, Japan.
authors.forename: Koki
authors.initials: K
authors.lastname: Nakamura
authors.affiliation: Medical Corporation Houeikai, Sekino Clinical Pharmacology Clinic, Tokyo, Japan.|Pharmaspur Inc., Tokyo, Japan.
authors.forename: Setsuo
authors.initials: S
authors.lastname: Hasegawa
mesh_terms: D000328:Adult; D000658:Amoxicillin / Q000009:adverse effects / Q000493:pharmacokinetics; D000900:Anti-Bacterial Agents / Q000009:adverse effects / Q000493:pharmacokinetics; D017291:Clarithromycin / Q000009:adverse effects / Q000493:pharmacokinetics; D004359:Drug Therapy, Combination / Q000379:methods; D064368:Healthy Volunteers; D016481:Helicobacter Infections / Q000188:drug therapy*; D016480:Helicobacter pylori / Q000187:drug effects; D006801:Humans; D008297:Male; D008795:Metronidazole / Q000009:adverse effects / Q000493:pharmacokinetics; D054328:Proton Pump Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics; D011758:Pyrroles / Q000009:adverse effects / Q000493:pharmacokinetics; D013449:Sulfonamides / Q000009:adverse effects / Q000493:pharmacokinetics; D016896:Treatment Outcome
chemical_list: C552956:1-(5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine; D000900:Anti-Bacterial Agents; D054328:Proton Pump Inhibitors; D011758:Pyrroles; D013449:Sulfonamides; D008795:Metronidazole; D000658:Amoxicillin; D017291:Clarithromycin
keywords: Drug interactions; Gastroenterology; Helicobacter pylori; Pharmacokinetics; Potassium-competitive acid blocker; Safety; TAK-438; Triple therapy; Vonoprazan