Zhou Sufeng, Xie Lijun, Zhou Chen, Zhao Yuqing, Wang Lu, Ding Sijia, Chen Juan, Zhu Bei, Su Mei, Shao Feng
Phase I Clinical Trial Unit, The First Affiliated Hospital with Nanjing Medical University, Nanjing 210029, China.
Jiangsu Carephar Pharmaceutical Co., Ltd, Nanjing 210000, China.
Eur J Pharm Sci. 2023 Nov 1;190:106578. doi: 10.1016/j.ejps.2023.106578. Epub 2023 Sep 4.
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 T of keverprazan was 1.25-1.75 h. C and AUC increased with the dose, and the t, 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 and AUC 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.
钾离子竞争性酸阻滞剂凯普拉赞是一种用于治疗酸相关性疾病的新型药物。
评估单次口服凯普拉赞在健康中国受试者中的安全性、药代动力学、药效学及食物效应。
在剂量递增的Ia期试验中，前8名受试者服用5毫克凯普拉赞，其他受试者依次进入10毫克、20毫克、40毫克、60毫克组，每组随机接受凯普拉赞（n = 8）、30毫克兰索拉唑（LSZ）（n = 2）或安慰剂（n = 2）。Ib期研究将受试者随机分为空腹-进食（n = 7）或进食-空腹（n = 7）组，以评估凯普拉赞的食物效应。
Ia期发生20例（35.71%）不良事件（AE），其中凯普拉赞组、安慰剂组和LSZ组分别有13例（32.50%）、3例（37.50%）和4例（50.00%）AE。Ib期发生4例（28.57%）AE。凯普拉赞的T为1.25 - 1.75小时。C和AUC随剂量增加，t、CL/F分别为6.00 - 7.17小时、88.8 - 198升/小时。胃内pH>5的维持时间比例（HTR）随剂量增加，但在20毫克时达到峰值。在30毫克LSZ组和5 - 60毫克凯普拉赞组中，24小时内胃内pH>5的HTR分别为57.1%±26.4%、7.9%±8.1%、26.2%±22.8%、80.2%±8.8%、88.1%±8.6%和93.0%±1.7%。进食与空腹状态下血浆中凯普拉赞C和AUC的几何平均比值（90%CI）分别为126.8%（109.0% - 147.5%）和134.9%（123.8% - 146.9%）。
凯普拉赞耐受性良好，20毫克时能提供显著稳定且持久的胃酸抑制效果。
