Keverprazan, a novel potassium-competitive acid blocker: Single ascending dose safety, tolerability, pharmacokinetics, pharmacodynamics and food effect in healthy subjects
Sufeng Zhou, Lijun Xie, Chen Zhou, Yuqing Zhao, Lu Wang, Sijia Ding, Juan Chen, Bei Zhu, Mei Su, Feng Shao
Abstract
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.