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

doi:10.1016/j.ejps.2023.106578

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

Eur J Pharm Sci. 2023 Nov 1:190:106578. doi: 10.1016/j.ejps.2023.106578. Epub 2023 Sep 4.

Authors

Sufeng Zhou¹, Lijun Xie¹, Chen Zhou¹, Yuqing Zhao¹, Lu Wang¹, Sijia Ding¹, Juan Chen¹, Bei Zhu¹, Mei Su², Feng Shao³

Affiliations

¹ Phase I Clinical Trial Unit, The First Affiliated Hospital with Nanjing Medical University, Nanjing 210029, China.
² Jiangsu Carephar Pharmaceutical Co., Ltd, Nanjing 210000, China. Electronic address: sumei@carephar.com.
³ Phase I Clinical Trial Unit, The First Affiliated Hospital with Nanjing Medical University, Nanjing 210029, China; Department of Clinical Pharmacology, Pharmacy College, Nanjing Medical University, Nanjing 211166, China. Electronic address: jsphshaofeng@hotmail.com.

PMID: 37666458
DOI: 10.1016/j.ejps.2023.106578

Abstract

Background: Keverprazan is a novel potassium-competitive acid blocker for the treatment of acid-related diseases.

Aims: To evaluate the safety, pharmacokinetics, pharmacodynamics, and food effect of single oral doses of keverprazan in healthy Chinese subjects.

Methods: 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.

Results: 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 T_max of keverprazan was 1.25-1.75 h. C_max and AUC increased with the dose, and the t_1/2, 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 C_max and AUC_0-∞ of keverprazan in plasma under the fed vs. fasting state were 126.8% (109.0%-147.5%) and 134.9% (123.8%-146.9%).

Conclusion: Keverprazan is tolerable, and provides significant stable and lasting inhibition efficacy of intragastric acidity at 20 mg.

Keywords: Gastroesophageal reflux disease; Keverprazan; Peptic ulcer; Pharmacodynamics; Pharmacokinetics; Potassium-competitive acid blocker.