内源性药物尿药生物等效性的试验设计和分析方法

Design and analysis of the bioequivalence trial of endogenous drugs based on urine data

目的以枸橼酸钾为例,介绍内源性药物的尿药生物等效性试验(BE)的设计和分析方法。方法根据FDA关于内源性药物BE研究相关指南及相关文献,以枸橼酸钾尿药BE研究为实例,探讨其研究流程、质量监控、剂量选择、样本采集以及数据分析等关键问题。结果在枸橼酸钾BE研究中,用单剂量、双交叉设计,对试验期间的饮食和活动进行标准化控制,用同一周期的给药前的内源性物质作为基线,校正尿药排泄量,最后用24 h尿药累积排泄量(Ae0-24h)、最大尿药排泄速率(Rmax)进行生物等效性分析。结论内源性药物BE研究,在设计上更为复杂,饮食和生理因素对结果影响大,需要基线校正,数据波动明显。尿药参数以Ae0-t和Rmax为主,而Tmax和T1/2没有实际意义。

Objective To introduce the design and analysis of the bioequivalence（BE） of endogenous drugs by the urine data of potassium citrate.Methods According to the FDA documents on the clinical BE study of endogenous drugs and other literature,the key issues including study flow,dietary and housing considerations,the dose choice,collection of samples and data analysis,were discussed in the bioequivalence study of potassium citrate.Results The BE of potassium citrate was designed as a single-dose and two-way crossover study.The subjects were assigned on a standardized diet and kept in a climate-controlled environment.The baseline urinary excretion（the average of at least two readings obtained on the two baseline days） of potassium and citrate were subtracted from the amount obtained on the drug dosing day,and the BE analysis was done according to the baseline-adjusted parameters（Ae0-24h： cumulative urinary excretion from 0 to 24 hours,Rmax： maximal rate of urinary excretion）.Conclusion It is a complicated design for the study of the BE of endogenous drug,and susceptible to diet and homeostatic mechanisms.The correction for baseline levels is mandatory,which leads significant variances of the parameters for analysis（Ae0-t and Rmax）.Other parameters such as Tmax and T1/2 are not applicable to evaluate BE.