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

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 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.

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.

Figure 1

Time course of mean plasma TAK-438 concentrations in the Phase I, randomised, double-blind, placebo-controlled, repeated-dose Japanese (top panel) and UK (bottom panel) studies in healthy male subjects receiving TAK-438 10–40 mg once daily at a fixed dose level for 7 consecutive days (Pharmacokinetic analysis set: Japan N = 60; UK N = 48).

Figure 2

Mean intragastric pH on Day 1 in healthy male subjects after a single dose of TAK-438 10–40 mg after overnight fasting in the Japanese (left panel) and UK (right panel) studies (Pharmacodynamic analysis set: Japan N = 60; UK N = 48).

Figure 3

Mean steady-state intragastric pH vs. time profiles after TAK-438 on Day 7 in the Japanese (left) and UK studies (right) in healthy male subjects receiving TAK-438 10–40 mg once daily after overnight fasting at a fixed dose level for 7 consecutive days (Pharmacodynamic analysis set: Japan N = 60; UK N = 48).

Figure 4

Mean 24-h (left panel) and night-time (12–24 h post dose in the Japanese study, 20:00–08:00 hours in the UK study; right panel) pH> 4 HTR in healthy male subjects receiving TAK-438 10–40 mg once daily at a fixed dose level for 7 consecutive days (Pharmacodynamic analysis set: Japan N = 60; UK N = 48).

Figure 5

Dose–response for pH >4 HTR (left) and pH>5 HTR (right) on Day 7 in the Japanese and UK studies in healthy male subjects receiving TAK-438 10–40 mg once daily at a fixed dose level for 7 consecutive days (Pharmacodynamic analysis set: Japan N = 60; UK N = 48).

Figure 6

Time course of mean serum gastrin (left), pepsinogen I (middle) and pepsinogen II (right) concentrations in healthy male subjects receiving TAK-438 10–40 mg once daily at a fixed dose level for 7 consecutive days in the Japanese (top three panels) and UK (bottom three panels) studies (Pharmacodynamic analysis set: Japan N = 60; UK N = 48).