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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

BACKGROUND: TAK-438 (vonoprazan) is a potassium-competitive acid blocker that reversibly inhibits gastric H(+), K(+)-ATPase. AIM: To evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of TAK-438 in healthy Japanese and non-Japanese men. METHODS: In two Phase I, randomised, doub...

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Autores principales: Jenkins, H, Sakurai, Y, Nishimura, A, Okamoto, H, Hibberd, M, Jenkins, R, Yoneyama, T, Ashida, K, Ogama, Y, Warrington, S
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Blackwell Publishing Ltd 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4654261/
https://www.ncbi.nlm.nih.gov/pubmed/25707624
http://dx.doi.org/10.1111/apt.13121
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author Jenkins, H
Sakurai, Y
Nishimura, A
Okamoto, H
Hibberd, M
Jenkins, R
Yoneyama, T
Ashida, K
Ogama, Y
Warrington, S
author_facet Jenkins, H
Sakurai, Y
Nishimura, A
Okamoto, H
Hibberd, M
Jenkins, R
Yoneyama, T
Ashida, K
Ogama, Y
Warrington, S
author_sort Jenkins, H
collection PubMed
description BACKGROUND: TAK-438 (vonoprazan) is a potassium-competitive acid blocker that reversibly inhibits gastric H(+), K(+)-ATPase. AIM: To evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of TAK-438 in healthy Japanese and non-Japanese men. METHODS: In 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). RESULTS: Plasma concentration–time profiles of TAK-438 at all dose levels showed rapid absorption (median T(max) ≤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 AUC(0-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. CONCLUSIONS: TAK-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.
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spelling pubmed-46542612015-11-27 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 Jenkins, H Sakurai, Y Nishimura, A Okamoto, H Hibberd, M Jenkins, R Yoneyama, T Ashida, K Ogama, Y Warrington, S Aliment Pharmacol Ther Randomised Clinical Trials BACKGROUND: TAK-438 (vonoprazan) is a potassium-competitive acid blocker that reversibly inhibits gastric H(+), K(+)-ATPase. AIM: To evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of TAK-438 in healthy Japanese and non-Japanese men. METHODS: In 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). RESULTS: Plasma concentration–time profiles of TAK-438 at all dose levels showed rapid absorption (median T(max) ≤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 AUC(0-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. CONCLUSIONS: TAK-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. Blackwell Publishing Ltd 2015-04 2015-02-23 /pmc/articles/PMC4654261/ /pubmed/25707624 http://dx.doi.org/10.1111/apt.13121 Text en © 2015 The Authors. Alimentary Pharmacology and Therapeutics published by John Wiley & Sons Ltd. http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
spellingShingle Randomised Clinical Trials
Jenkins, H
Sakurai, Y
Nishimura, A
Okamoto, H
Hibberd, M
Jenkins, R
Yoneyama, T
Ashida, K
Ogama, Y
Warrington, S
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
title 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
title_full 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
title_fullStr 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
title_full_unstemmed 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
title_short 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
title_sort 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
topic Randomised Clinical Trials
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4654261/
https://www.ncbi.nlm.nih.gov/pubmed/25707624
http://dx.doi.org/10.1111/apt.13121
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