Effect of Therapeutic and Supratherapeutic Doses of Vonoprazan on the QT/QTc Interval in a Phase I Randomized Study in Healthy Subjects

Astruc, B; Jenkins, Helen; Jenkins, Richard O.

doi:10.1111/cts.12452

Cited by 9 publications

(15 citation statements)

References 15 publications

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“…There is evidence that vonoprazan exhibits a wide therapeutic index; it has been demonstrated that a single dose of vonoprazan 120 mg was well tolerated 40. 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.…”

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

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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.

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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

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“…Therefore, vonoprazan is a strong acid blocker that has rapid, stable, and long-lasting effects 35,46,48,52 and these effects were stronger than conventional PPIs 35,41,45,48,52,53 and prototype P-CAB. 41 Phase I studies of single ascending 45 and multiple repeat doses 46 in Japan and the United Kingdom revealed that vonoprazan was well-tolerated at single doses of 1-120 mg and at repeat doses of 10-40 mg. 54 The mean percentage of time that patients had a intragastric pH above 4 after multiple doses of 40 mg vonoprazan was 85.3% and 100.0% during the day and 86.5% and 100.0% at night (21:00-9:00) on days 1 and 7, respectively. 46…”

Section: Pharmacodynamicsmentioning

confidence: 93%

Potent Potassium-competitive Acid Blockers: A New Era for the Treatment of Acid-related Diseases

Oshima

Miwa

2018

J Neurogastroenterol Motil

123

107

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Conventional proton pump inhibitors (PPIs) are used as a first-line therapy to treat acid-related diseases worldwide. However, they have a number of limitations including slow onset of action, influence by cytochrome P450 polymorphisms, unsatisfactory effects at night, and instability in acidic conditions. Alternative formulations of conventional PPIs have been developed to overcome these problems; however, these drugs have only introduced small advantages for controlling acid secretion compared to conventional PPIs. Potassium-competitive acid blockers (P-CABs) were developed and have beneficial effects including rapid, long-lasting, and reversible inhibition of the gastric hydrogen potassium ATPase, the proton pump of the stomach. Vonoprazan was recently innovated as a novel, orally active P-CAB. It is currently indicated for the treatment of gastric and duodenal ulcers, reflux esophagitis, and prevention of low-dose aspirin- or nonsteroidal anti-inflammatory drug-related gastric and duodenal ulcer recurrence in Japan. Vonoprazan does not require enteric coating as it is acid-stable, and it can be taken without food because it is quickly absorbed. Vonoprazan accumulates in parietal cells under both acidic and neutral conditions. It does not require an acidic environment for activation, has long-term stability at the site of action, and has satisfactory safety and tolerability. Thus, vonoprazan may address the unmet medical need for the treatment of acid-related diseases.

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“…Our safety and tolerability findings are consistent with published data from other studies of vonoprazan in 212 healthy volunteers given daily doses of up to 40 mg for up to 7 days, with no safety signals. 13 , 27 , 28 , 29 …”

Section: Discussionmentioning

confidence: 99%

The Effect of Food on the Pharmacokinetics of the Potassium‐Competitive Acid Blocker Vonoprazan

Mulford¹,

Leifke²,

Hibberd³

et al. 2021

Clinical Pharm in Drug Dev

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Herein,we report a food-effect study of vonoprazan,an oral potassium-competitive acid blocker.In a phase 1,randomized, open-label, crossover study, healthy subjects received a single 20-mg dose of vonoprazan either following an overnight fast or 30 minutes after a high-fat breakfast. Plasma vonoprazan levels were determined at 0 hour and at 17 subsequent assessment points up to 48 hours after dosing. After a 5-day washout, subjects received a second 20-mg vonoprazan dose in the alternative fed/fasted state (identical process repeated). Twenty-four subjects completed the study. Vonoprazan exposure was not meaningfully affected by food. Geometric mean ratios for maximum concentration, area under the concentration-time curve from time 0 to 24 hours, and area under the plasma concentration-time curve extrapolated to infinity obtained under fed and fasting conditions were 1.05 (90% confidence interval, 0.98-1.12), 1.13 (1.09-1.18), and 1.15 (1.11-1.19), respectively. Four subjects experienced 6 adverse events that were all mild and considered unrelated to the study drug. Vonoprazan can be administered without regard to food intake.

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Effect of Therapeutic and Supratherapeutic Doses of Vonoprazan on the QT/QTc Interval in a Phase I Randomized Study in Healthy Subjects

Cited by 9 publications

References 15 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

Potent Potassium-competitive Acid Blockers: A New Era for the Treatment of Acid-related Diseases

The Effect of Food on the Pharmacokinetics of the Potassium‐Competitive Acid Blocker Vonoprazan

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