两种培哚普利叔丁胺片在健康中国受试者空腹和进食条件下的生物等效性研究：一项随机、开放标签、单剂量、交叉试验。

Bioequivalence study of two perindopril tert-butylamine tablet formulations in healthy Chinese subjects under fasting and fed conditions: A randomized, open-label, single-dose, crossover trial.

机构信息

Phase I Clinical Trial Unit, General Hospital of Northern Theater Command, Shenyang, 110840, China.

出版信息

Biomed Pharmacother. 2021 Mar;135:111221. doi: 10.1016/j.biopha.2021.111221. Epub 2021 Feb 1.

DOI:10.1016/j.biopha.2021.111221

PMID:33433351

Abstract

BACKGROUND

To evaluate the bioequivalence between test and reference formulations of perindopril tert-butylamine under fasting and fed conditions and to assess their pharmacokinetic (PK) and safety profiles.

METHOD

A randomized, open-label, single-dose, crossover trial was conducted in healthy Chinese subjects. Test or reference perindopril tert-butylamine tablets (4 mg) were randomly given to subjects under fasting (2-period crossover, with an administration sequence of test tablet (T), reference tablet (R) or RT) and fed (4-period crossover, with an administration sequence of TRTR or RTRT) conditions, while each single administration was followed by a 14-day washout period. The plasma concentrations and corresponding non-compartmental PK parameters of perindopril and perindoprilat were determined. The two formulations were considered to be bioequivalent if the 90 % confidence intervals (CIs) of the geometric mean (GM) ratio (test/reference) for C, AUC, and AUC (perindopril) was both within the range of 80-125 %. Safety assessments including vital signs, physical examination, laboratory examination, 12-lead ECG and reports of treatment emergent adverse events (TEAEs) were carefully documented.

RESULTS

A total of 64 subjects (32 in each trial) were randomized and all completed the trials. Regardless of fasting or fed trials, the PK characteristics of perindopril and perindoprilat for the test formulation were similar to those of the reference formulation (all P > 0.05). The 90 % CIs of the geometric mean (GM) ratio for C, AUC and AUC, respectively, were 92.86-106.81 %, 98.44-102.88 % and 98.48-103.02 % under the fasting condition and 90.64-110.04 %, 96.95-101.90 % and 96.83-101.78 % under the fed condition, which were both within the pre-specified range of 80-125 %. A total of 10 (31.3 %) fasted subjects and 11 (34.4 %) fed subjects experienced 11 and 24 TEAEs, respectively, all of which were within the severity of grade 1. The incidence of TEAEs and drug-related TEAEs were similar between test and reference formulations (all P > 0.05) and no serious TEAEs or deaths occurred during the trials.

CONCLUSIONS

The test and reference formulations of perindopril tert-butylamine tablets (4 mg) were bioequivalent and well tolerated in healthy Chinese subjects under fasting and fed conditions.

摘要

背景

评估培哚普利叔丁胺在空腹和进食条件下的试验制剂与参比制剂的生物等效性，并评估其药代动力学（PK）和安全性特征。

方法

在中国健康受试者中进行了一项随机、开放标签、单剂量、交叉试验。空腹（2 期交叉，给药顺序为试验片（T）、参比片（R）或 RT）和进食（4 期交叉，给药顺序为 TRTR 或 RTRT）条件下随机给予受试者试验或参比培哚普利叔丁胺片（4mg），每次单剂量后进行 14 天洗脱期。测定培哚普利和培哚普利拉的血浆浓度和相应的非房室 PK 参数。如果试验制剂和参比制剂的 C （t）、AUC 和 AUC（perindopril）的几何均数（GM）比值（试验/参比）的 90%置信区间（CI）均在 80-125%范围内，则认为两种制剂具有生物等效性。仔细记录了包括生命体征、体格检查、实验室检查、12 导联心电图和治疗中出现的不良事件（TEAEs）报告在内的安全性评估。

结果

共有 64 名受试者（每个试验 32 名）被随机分配，均完成了试验。无论空腹或进食试验，试验制剂的培哚普利和培哚普利拉 PK 特征均与参比制剂相似（均 P>0.05）。空腹条件下，C、AUC 和 AUC 的 GM 比值的 90%CI 分别为 92.86-106.81%、98.44-102.88%和 98.48-103.02%，进食条件下分别为 90.64-110.04%、96.95-101.90%和 96.83-101.78%，均在 80-125%的预定范围内。10 名（31.3%）空腹受试者和 11 名（34.4%）进食受试者分别发生 11 次和 24 次 TEAEs，均为 1 级严重程度。试验制剂和参比制剂的 TEAEs 发生率和药物相关 TEAEs 发生率相似（均 P>0.05），试验过程中未发生严重 TEAEs 或死亡。