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

Jenkins, Helen; Jenkins, Richard O.; Patat, Alain

doi:10.1007/s40261-016-0488-6

Cited by 24 publications

(29 citation statements)

References 9 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…There is also evidence that multiple doses of 40 mg per day were well tolerated 41. Interaction of vonoprazan and clarithromycin, an inhibitor of CYP3A4, resulted in an almost twofold increase in oral bioavailability, but this was not associated with a significant alteration in efficacy and/or safety42 as plasma concentrations remained within the therapeutic window. In addition, given that the dosing interval of vonoprazan is 24 hours and that the accumulation factor is two when the dosing interval is equal to the half-life, which is 9.4 hours, vonoprazan accumulation under CYP3A4 inhibition will be considerably lower than twofold.…”

Section: Discussionmentioning

confidence: 99%

Phase III, randomised, double-blind, multicentre study to evaluate the efficacy and safety of vonoprazan compared with lansoprazole in Asian patients with erosive oesophagitis

Xiao

Zhang

Dai

et al. 2019

Gut

124

View full text Add to dashboard Cite

ObjectiveTo establish the non-inferior efficacy of vonoprazan versus lansoprazole in the treatment of Asian patients with erosive oesophagitis (EO).DesignIn this phase III, double-blind, multicentre study, patients with endoscopically confirmed EO were randomised 1:1 to receive vonoprazan 20 mg or lansoprazole 30 mg, once daily for up to 8 weeks. The primary endpoint was EO healing rate at 8 weeks. The secondary endpoints were EO healing rates at 2 and 4 weeks. Safety endpoints included treatment-emergent adverse events (TEAEs).ResultsIn the vonoprazan (n=238) and lansoprazole (n=230) arms, 8-week EO healing rates were 92.4% and 91.3%, respectively (difference 1.1% (95% CI –3.822% to 6.087%)). The respective 2-week EO healing rates were 75.0% and 67.8% (difference 7.2% (95% CI –1.054% to 15.371%)), and the respective 4-week EO healing rates were 85.3% and 83.5% (difference 1.8% (95% CI –4.763% to 8.395%)). In patients with baseline Los Angeles classification grade C/D, 2-week, 4-week and 8-week EO healing rates were higher with vonoprazan versus lansoprazole (2 weeks: 62.2% vs 51.5%, difference 10.6% (95% CI –5.708% to 27.002%); 4 weeks: 73.3% vs 67.2%, difference 6.2% (95% CI –8.884 to 21.223); and 8 weeks: 84.0% vs 80.6%, difference 3.4% (95% CI –9.187% to 15.993%)). Overall, EO healing rates appeared higher with vonoprazan versus lansoprazole. TEAE rates were 38.1% and 36.6% in the vonoprazan and lansoprazole group, respectively.ConclusionOur findings demonstrate the non-inferior efficacy of vonoprazan versus lansoprazole in terms of EO healing rate at 8 weeks in this population. Safety outcomes were similar in the two treatment arms.Trial registration numberNCT02388724.

show abstract

Section: Discussionmentioning

confidence: 99%

Phase III, randomised, double-blind, multicentre study to evaluate the efficacy and safety of vonoprazan compared with lansoprazole in Asian patients with erosive oesophagitis

Xiao

Zhang

Dai

et al. 2019

Gut

124

View full text Add to dashboard Cite

show abstract

“…Thus far, the DDI investigation of vonoprazan mainly concerned CYP3A4 and CYP2C19, with unconvincing consequences. In the triple regimens to eradicate H. pylori infection, whether the coadministration of vonoprazan and clarithromycin (CYP3A4 inhibitor) would have a mutual effect remains debatable (Jenkins et al, 2017;Sugimoto and Yamaoka, 2018). Additionally, observed that vonoprazan could attenuate the function of clopidogrel, not depending on the CYP2C19 or CYP3A4 genotypes.…”

Section: Discussionmentioning

confidence: 99%

Cytochrome P450-Based Drug-Drug Interactions of Vonoprazan In Vitro and In Vivo

Wang

et al. 2020

Front. Pharmacol.

View full text Add to dashboard Cite

Background: Vonoprazan fumarate is a potassium-competitive acid blocker that was developed as a novel acid-suppressing drug for multiple indications. As a potential alternative to proton-pump inhibitors, the determination of the drug-drug interactions is vital for further applications. Probe drug cocktails are a type of rapid, economical, and efficient approach for evaluating cytochrome P450 enzyme activities. Since vonoprazan is metabolized partly by cytochrome P450, cocktails were used to study CYP-based drugdrug interactions. Methods: This study was conducted both in vitro and in vivo. In the in vitro study of rat liver microsomes, ultra-performance liquid chromatography coupled to tandem mass spectrometry was utilized to assess the reversible inhibition of cytochrome P450 by vonoprazan by determining the concentration of probe drugs (phenacetin, bupropion, tolbutamide, dextromethorphan, midazolam, chlorzoxazone). The differences in the levels of probe drugs between the rat groups with or without vonoprazan administration were also tested in the rats. Results: In vitro analysis revealed that the IC 50 values of midazolam, tolbutamide, dextromethorphan, and bupropion in rat microsomes were 22.48, 18.34, 3.62, and 3.68 mM, respectively, while chlorzoxazone and phenacetin displayed no inhibition. In vivo analysis revealed that midazolam, bupropion, dextromethorphan, and tolbutamide showed significant (P < 0.05) differences in distinct pharmacokinetic parameters after vonoprazan administration, while those of chlorzoxazone and phenacetin were not significantly different. Conclusion: The in vitro and in vivo results indicated that vonoprazan can inhibit CYP3A4, CYP2C9, CYP2D6, and CYP2B6, suggesting that the coadministration of vonoprazan with cytochrome P450 substrates should be performed cautiously in clinical settings.

show abstract

“…However, CYP3A4 expression in the human liver is higher in females than males [22]. The concentration of vonoprazan is increased by co‐administration of clarithromycin which is also metabolized by CYP3A4 [23]. Therefore, gender differences in CYP3A4 expression and clarithromycin co‐administration may be partially responsible for results showing greater success in males.…”

Section: Discussionmentioning

confidence: 99%

Pre‐treatment with proton pump inhibitors decreases the success of primary Helicobacter pylori eradication using a vonoprazan‐based regimen

Shinozaki

Osawa

Sakamoto

et al. 2018

The Kaohsiung J of Med Scie

View full text Add to dashboard Cite

Vonoprazan-based regimens have improved the rate of successful Helicobacter pylori (H. pylori) eradication, but it has not reached 100%. The aim of this study is to clarify significant predictors of successful H. pylori eradication using a vonoprazan-based regimen. In this retrospective cohort study, 174 patients who underwent primary H. pylori eradication therapy were included. All patients underwent esophagogastroduodenoscopy before treatment. The vonoprazan-based regimen includes amoxicillin 750 mg, clarithromycin 200 mg and vonoprazan 20 mg twice daily for one week. Pre-treatment with a proton pump inhibitor (PPI) was defined as continued PPI use for more than four weeks prior to eradication therapy. The rates of successful eradication were 83% (145/174) in intention-to-treat analysis and 85% (145/171) in per-protocol analysis. Predictors of successful eradication among 171 patients were evaluated in per-protocol analysis. In univariate analysis, male gender was a significant positive predictor of successful eradication (odds ratio [OR] 3.813, 95% confidence interval [CI] 1.363-10.663, p = 0.010) and pre-treatment with PPIs was a negative predictor (OR 0.193, 95%CI 0.076-0.485, p < 0.001). In multivariate analysis, male gender remained a positive predictor (OR 3.826, 95%CI 1.317-11.116, p = 0.013), and pre-treatment with PPIs (OR 0.232, 95%CI 0.087-0.615, p = 0.003) remained a negative predictor. In conclusion, pre-treatment with PPIs before eradication therapy decreases the rate of successful eradication. Therefore, it may be desirable to discontinue pre-treatment with PPIs prior to eradication therapy, because of the potential to improve the rate of successful eradication.

show abstract

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

Cited by 24 publications

References 9 publications

Phase III, randomised, double-blind, multicentre study to evaluate the efficacy and safety of vonoprazan compared with lansoprazole in Asian patients with erosive oesophagitis

Phase III, randomised, double-blind, multicentre study to evaluate the efficacy and safety of vonoprazan compared with lansoprazole in Asian patients with erosive oesophagitis

Cytochrome P450-Based Drug-Drug Interactions of Vonoprazan In Vitro and In Vivo

Pre‐treatment with proton pump inhibitors decreases the success of primary Helicobacter pylori eradication using a vonoprazan‐based regimen

Contact Info

Product

Resources

About