Randomised clinical trial: safety, tolerability, pharmacokinetics and pharmacodynamics of repeated doses of TAK‐438 (vonoprazan), a novel potassium‐competitive acid blocker, in healthy male subjects

Abstract

BackgroundTAK-438 (vonoprazan) is a potassium-competitive acid blocker that reversibly inhibits gastric H+, K+-ATPase.AimTo evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of TAK-438 in healthy Japanese and non-Japanese men.MethodsIn two Phase I, randomised, double-blind, placebo-controlled studies, healthy men (Japan N = 60; UK N = 48) received TAK-438 10–40 mg once daily at a fixed dose level for 7 consecutive days. Assessments included safety, tolerability, pharmacokinetics and pharmacodynamics (intragastric pH).ResultsPlasma concentration–time profiles of TAK-438 at all dose levels showed rapid absorption (median Tmax ≤2 h). Mean elimination half-life was up to 9 h. Exposure was slightly greater than dose proportional, with no apparent time-dependent inhibition of metabolism. There was no important difference between the two studies in AUC0-tau on Day 7. TAK-438 caused dose-dependent acid suppression. On Day 7, mean 24-h intragastric pH>4 holding time ratio (HTR) with 40 mg TAK-438 was 100% (Japan) and 93.2% (UK), and mean night-time pH>4 HTR was 100% (Japan) and 90.4% (UK). TAK-438 was well tolerated. The frequency of adverse events was similar at all dose levels and there were no serious adverse events. There were no important increases in serum alanine transaminase activity. Serum gastrin and pepsinogen I and II concentrations increased with TAK-438 dose.ConclusionsTAK-438 in multiple rising oral dose levels of 10–40 mg once daily for 7 days was safe and well tolerated in healthy men and caused rapid, profound and sustained suppression of gastric acid secretion throughout each 24-h dosing interval. Clinicaltrials.gov identifiers: NCT02123953 and NCT02141711.

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

“…Similar to data from previous studies,4, 5 plasma concentrations of vonoprazan increased in a slightly more than dose‐proportional manner. Thorough QT studies should ensure that dose–response and concentration–response relationships for QTc prolongation are fully characterized, including exploration of concentrations higher than those anticipated in therapeutic use.…”

“…Another limitation is that the current study evaluated the effects on the QT interval after only a single dose of vonoprazan, while the recommended oral dose of vonoprazan is 10 mg or 20 mg once daily for 4 weeks to 8 weeks, depending on the indication 3. However, in a phase I study of vonoprazan 10 mg to 40 mg once daily for 7 consecutive days in healthy Japanese males ( N = 60), there was no clinically relevant accumulation of vonoprazan or its metabolites with similar pharmacokinetic parameters on Days 1 and 7 5. Although the long‐term effects of vonoprazan on QT/QTc in patients cannot be determined from the current study, long‐term clinical studies with vonoprazan lasting up to 2 years have not identified clinically meaningful changes in serum electrolyte levels or ECG parameters (unpublished data; OCT‐301, Mizokami Y, Oda K, Funao N, Nishimura A, Soen S, Kawai T, Ashida K, et al .…”

“…Clinical studies of single ascending doses4 (1–120 mg), as well as multiple repeated‐doses5 (10–40 mg) of vonoprazan, confirmed its tolerability in healthy subjects, with a rapid onset of action (<4 h) and prolonged duration (24 h) of action. Vonoprazan has a potent and long‐lasting antisecretory effect on H+, K+‐ATPase due to its high accumulation and slow clearance from gastric tissue 1…”

“…Electrocardiogram (ECG) parameters for vonoprazan in clinical trials have not shown any clinically meaningful QT/QTc prolongation 4, 5, 9, 10, 11, 12, 13, 14. Despite the lack of cardiac arrhythmic events in the extensive clinical development program, a thorough QT study was conducted to provide a definitive assessment of the effects of vonoprazan on the QT interval.…”

Risk Factors for Delayed Ulcer Healing after Endoscopic Submucosal Dissection of Gastric Neoplasms

“…Vonoprazan is one of the new class of acid-suppressing agents that may be used as an alternative to PPIs as blocker of gastric hydrogen-potassium adenosine triphosphatase, which inhibits the critical final step in gastric acid secretion by reversing K+-competitive ionic binding. The pharmaceutical advantages of P-CAB over PPIs include more rapid, stronger and longer-lasting inhibition of gastric acid secretion after administration [7,15,16]. For the treatment of peptic ulcers, Miwa et al reported that a 20 mg dose of vonoprazan had a similar tolerability profile as a 30 mg dose of lansoprazole, and was not inferior to lansoprazole with respect to gastric ulcer healing [17].…”