Keverprazan, a novel potassium-competitive acid blocker: Single ascending dose safety, tolerability, pharmacokinetics, pharmacodynamics and food effect in healthy subjects

Keverprazan is a novel potassium-competitive acid blocker for the treatment of acid-related diseases. To evaluate the safety, pharmacokinetics, pharmacodynamics, and food effect of single oral doses of keverprazan in healthy Chinese subjects. In the dose-escalated phase Ia trial, the first 8 subjects received keverprazan 5 mg, the others successively entered 10 mg, 20 mg, 40 mg, 60 mg groups and were randomized to receive keverprazan (n=8), lansoprazole (LSZ) 30 mg (n=2) or placebo (n=2) in each dose group. The phase Ib study randomly enrolled subjects to the fasting-fed (n=7) or fed-fasting (n=7) groups for evaluating the food effect of keverprazan. Twenty (35.71%) adverse events (AEs) occurred in phase Ia, including 13 (32.50%), 3 (37.50%), and 4 (50.00%) AEs in the keverprazan, placebo, and LSZ groups, respectively. Four (28.57%) AEs occurred in Phase Ib. The Tmax of keverprazan was 1.25-1.75 h. Cmax and AUC increased with the dose, and the t1/2, CL/F were 6.00-7.17 h, 88.8-198 L/h, respectively. The intragastric pH >5 holding-time ratio (HTR) increased with the dose but reached a ceiling at 20 mg. In the 30 mg LSZ and 5-60 mg keverprazan groups, the intragastric pH >5 HTRs during 24 h were 57.1%±26.4%, 7.9%±8.1%, 26.2%±22.8%, 80.2%±8.8%, 88.1%±8.6%, and 93.0%±1.7%, respectively. The geometric mean ratios (90% CI) of Cmax and AUC0-∞ of keverprazan in plasma under the fed vs. fasting state were 126.8% (109.0%-147.5%) and 134.9% (123.8%-146.9%). Keverprazan is tolerable, and provides significant stable and lasting inhibition efficacy of intragastric acidity at 20 mg.