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

Sakurai, Yuuichi; Shiino, Madoka; Okamoto, Hiroyuki; Nishimura, Akira; Nakamura, Koki; Hasegawa, Setsuo

doi:10.1007/s12325-016-0374-x

Cited by 32 publications

(24 citation statements)

References 27 publications

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“…This result is the same as that of a previous Japanese study of a PPI (44). Although vonoprazan increases the blood concentration of clarithromycin (45) and stabilizes clarithromycin in gastric juice by suppressing gastric acid secretion (46), an increase in only the clarithromycin dose does not have a positive impact on H. pylori eradication.…”

Section: ) Efficacy Of Vonoprazan For First-line Eradicationsupporting

confidence: 87%

Efficacy of Vonoprazan for <i>Helicobacter pylori</i> Eradication

2020

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Helicobacter pylori can infect the gastric mucosa and cause chronic inflammation, resulting in various diseases, including gastric cancer. Eradication of H. pylori in all infected subjects is recommended; however, the number of H. pylori strains with antibiotic resistance has increased, and the eradication rate has decreased. Vonoprazan, a potassium-competitive acid blocker, produces a stronger acid-inhibitory effect than proton pump inhibitors (PPIs). The H. pylori eradication rate with vonoprazan was found to be higher than that with PPIs. The H. pylori eradication rate with vonoprazan-based triple therapy (vonoprazan, amoxicillin, and clarithromycin) was approximately 90% and had an incidence of adverse events similar to that of PPIs. We review the current situation of H. pylori eradication in Japan, the first country in which vonoprazan was made available.

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Section: ) Efficacy Of Vonoprazan For First-line Eradicationsupporting

confidence: 87%

Efficacy of Vonoprazan for <i>Helicobacter pylori</i> Eradication

2020

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“…Another possible explanation for the CLA-resistant eradication difference observed between the VA-dual and VAC-triple therapies regards the pharmacokinetic interaction of vonoprazan and CLA. Because both vonoprazan and CLA are metabolised by the same hepatic enzyme (cytochrome P450 3A4), administering both drugs together increases the maximum plasma concentration and the area under the plasma concentration–time curve of vonoprazan by 1.5-fold to 1.9-fold in comparison with the administration of vonoprazan alone 40. Vonoprazan has a strong gastric acid inhibitory effect and the gastric pH level often exceeds 7 even when administered alone 9 27.…”

Section: Discussionmentioning

confidence: 99%

Seven-day vonoprazan and low-dose amoxicillin dual therapy as first-line Helicobacter pylori treatment: a multicentre randomised trial in Japan

Suzuki

Gotoda

Kusano

et al. 2020

Gut

171

237

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ObjectiveTo date, no randomised trials have compared the efficacy of vonoprazan and amoxicillin dual therapy with other standard regimens for Helicobacter pylori treatment. This study aimed to investigate the efficacy of the 7-day vonoprazan and low-dose amoxicillin dual therapy as a first-line H. pylori treatment, and compared this with vonoprazan-based triple therapy.DesignThis prospective, randomised clinical trial was performed at seven Japanese institutions. Patients with H. pylori–positive culture test and naive to treatment were randomly assigned in a 1:1 ratio to either VA-dual therapy (vonoprazan 20 mg+amoxicillin 750 mg twice/day) or VAC-triple therapy (vonoprazan 20 mg+amoxicillin 750 mg+clarithromycin 200 mg twice/day) for 7 days, with stratification by age, sex, H. pylori antimicrobial resistance and institution. Eradication success was evaluated by 13C-urea breath test at least 4 weeks after treatment.ResultsBetween October 2018 and June 2019, 629 subjects were screened and 335 were randomised. The eradication rates of VA-dual and VAC-triple therapies were 84.5% and 89.2% (p=0.203) by intention-to-treat analysis, respectively, and 87.1% and 90.2% (p=0.372) by per-protocol analysis, respectively. VA-dual was non-inferior to VAC-triple in the per-protocol analysis. The eradication rates in strains resistant to clarithromycin for VA-dual were significantly higher than those for VAC-triple (92.3% vs 76.2%; p=0.048). The incidence of adverse events was equal between groups.ConclusionThe 7-day vonoprazan and low-dose amoxicillin dual therapy provided acceptable H. pylori eradication rates and a similar effect to vonoprazan-based triple therapy in regions with high clarithromycin resistance.Trial registration numberUMIN000034140.

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“…Although CYP3A4 is partly involved in the formation of cycloguanil from proguanil, Sakurai et al . excluded the possibility of CYP3A4‐medaited DDI by vonoprazan based on a clinical study of vonoprazan with clarithromycin . By contrast, vonoprazan, but not esomeprazole, attenuated the antiplatelet function of prasugrel, which is metabolically activated mainly by CYP2B6 and CYP3A4 .…”

Section: Discussionmentioning

confidence: 99%

Effects of proton pump inhibitors, esomeprazole and vonoprazan, on the disposition of proguanil, a CYP2C19 substrate, in healthy volunteers

Funakoshi

Tomoda

Kudo

et al. 2019

Brit J Clinical Pharma

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Aims: Vonoprazan, a new class of potassium-competitive proton pump inhibitors has been found to attenuate the antiplatelet function of clopidogrel in a recent clinical study, despite weak in vitro activity against CYP2C19. To elucidate the mechanism of this interaction, the present study investigated the effects of esomeprazole and vonoprazan on the pharmacokinetics of proguanil, a CYP2C19 substrate.Methods: Seven healthy male volunteers (CYP2C19 extensive metabolizers) received a single oral administration of 100 mg proguanil/250 mg atovaquone (control phase), oral esomeprazole (20 mg) for 5 days followed by proguanil/atovaquone (esomeprazole phase) and oral vonoprazan (20 mg) for 5 days followed by proguanil/atovaquone (vonoprazan phase). Concentrations of proguanil and its metabolite, cycloguanil, in plasma and urine in each phase were determined using liquid chromatography-tandem mass spectrometry. Results: Coadministration with proton pump inhibitors resulted in increase and decrease in the area under the plasma concentration-time curve (AUC) of proguanil and cycloguanil, respectively, significantly reducing their AUC ratio (cycloguanil/proguanil) to 0.317-fold (95% confidence interval [CI] 0.256-0.379) and 0.507-fold (95% CI 0.409-0.605) in esomeprazole phase and vonoprazan phase, respectively. Esomeprazole and vonoprazan also significantly reduced the apparent formation clearance (cumulative amount of cycloguanil in urine divided by AUC of proguanil) to 0.324-fold (95% CI 0.212-0.436) and 0.433-fold (95% CI 0.355-0.511), respectively, without significant changes in renal clearance of proguanil and cycloguanil.Conclusions: Although further studies are needed, both esomeprazole and vonoprazan potentially inhibit CYP2C19 at clinical doses, suggesting caution in the coadministration of these drugs with CYP2C19 substrates. KEYWORDS cytochrome P450, drug interactions, drug metabolism Principal Investigator (PI) statement: The authors confirm that the PI for this paper is Dr Kenichi Furihata and that he had direct clinical responsibility for patients.

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

Abstract: JapicCTI-153102.

Cited by 32 publications

References 27 publications

Efficacy of Vonoprazan for <i>Helicobacter pylori</i> Eradication

Efficacy of Vonoprazan for <i>Helicobacter pylori</i> Eradication

Seven-day vonoprazan and low-dose amoxicillin dual therapy as first-line Helicobacter pylori treatment: a multicentre randomised trial in Japan

Effects of proton pump inhibitors, esomeprazole and vonoprazan, on the disposition of proguanil, a CYP2C19 substrate, in healthy volunteers

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