健康中国受试者单次及多次口服替戈拉赞的安全性、耐受性和药代动力学。

Safety, Tolerability and Pharmacokinetics of Single Ascending and Multiple Oral Doses of Tegoprazan in Healthy Chinese Subjects.

机构信息

Phase I Clinical Research Center, Huashan Hospital, Fudan University, No.12 in Wurumuqi Road, Jingan Area, Shanghai, China.

School of Pharmacy, Fudan University, Shanghai, China.

出版信息

Clin Drug Investig. 2021 Jan;41(1):89-97. doi: 10.1007/s40261-020-00986-4. Epub 2020 Dec 23.

DOI:10.1007/s40261-020-00986-4

PMID:33355910

Abstract

BACKGROUND AND OBJECTIVES

Tegoprazan is one of the potassium-competitive acid blockers (P-CABs). It exhibits its anti-secretory effects by competitively and reversibly blocking the availability of K of the H, K-ATPase. This study was designed to investigate the safety and pharmacokinetics of tegoprazan in healthy Chinese subjects.

METHODS

Thirty-eight healthy Chinese subjects were recruited in this randomized, single-center, double-blind, placebo-controlled study, with a single ascending dose of 50, 100, 200 mg and a multiple dose of 100 mg for 10 days. The plasma concentration of tegoprazan was determined by a validated liquid chromatography tandem mass spectrometry (LC-MS/MS) method. Pharmacokinetics were evaluated via non-compartmental and compartmental model analysis. Safety was assessed by physical examinations, vital signs, clinical laboratory tests, and electrocardiograms.

RESULTS

No serious adverse event was observed in this study. After single-dose administration (50, 100 and 200 mg), tegoprazan was rapidly absorbed with a median maximum measure plasma concentration (T) at 0.5 h and declined with a terminal (elimination) half-life (t) of 3.87-4.57 h. The maximum measured plasma concentration (C) for tegoprazan was 813.80, 1494.60 and 2829.00 ng/mL. Meanwhile, the corresponding area under the concentration-time curve (AUC) from time zero to infinity (AUC) was 2761.00, 5980.05 and 11,044.72 ng∙h/mL in 50, 100, 200 mg group, respectively. Dose-dependent increase was observed in the value of C and AUC after administration of tegoprazan 50 to 200 mg. The two-compartment model well described the pharmacokinetic profile of tegoprazan. In the steady state, no accumulation was found after repeated administration at the 100-mg dose level. No experimental differences were found based on gender.

CONCLUSIONS

Tegoprazan was well tolerated in the dose range of 50-200 mg in single- and 100 mg in multiple-dose studies. Tegoprazan shows dose linearity with oral administration after a single dose of 50 to 200 mg and less drug accumulation after 10 days of continuous administration in 100 mg.

摘要

背景与目的

替泊拉唑是钾离子竞争性酸阻滞剂（P-CABs）之一。它通过竞争性和可逆地阻断 H + ，K-ATP 酶的 K + 可用性来发挥其抗分泌作用。本研究旨在考察替泊拉唑在中国健康受试者中的安全性和药代动力学。

方法

本研究为随机、单中心、双盲、安慰剂对照研究，共纳入 38 例健康受试者，单剂量递增至 50、100、200 mg，10 天内重复给予 100 mg。替泊拉唑的血药浓度采用经验证的液相色谱串联质谱（LC-MS/MS）法测定。非房室模型和房室模型分析用于药代动力学评价。通过体格检查、生命体征、临床实验室检查和心电图评估安全性。

结果

本研究中未观察到严重不良事件。单次给药（50、100 和 200 mg）后，替泊拉唑迅速吸收，中位最大实测血浆浓度（T）为 0.5 h，终末（消除）半衰期（t）为 3.87-4.57 h。替泊拉唑的最大实测血浆浓度（C）分别为 813.80、1494.60 和 2829.00 ng/mL。同时，50、100、200 mg 组替泊拉唑的 0 至无穷时浓度-时间曲线下面积（AUC）分别为 2761.00、5980.05 和 11044.72 ng·h/mL。替泊拉唑 50-200 mg 给药后，C 和 AUC 值呈剂量依赖性增加。双室模型很好地描述了替泊拉唑的药代动力学特征。在稳态下，100 mg 剂量水平重复给药后未发现蓄积。基于性别未发现实验差异。