Portolés Antonio, Filipe Augusto, Almeida Susana, Terleira Ana, Vallée François, Vargas Emilio
Servicio de Farmacología Clínica, Hospital Clinico San Carlos, Madrid (Spain).
Arzneimittelforschung. 2005;55(4):212-7. doi: 10.1055/s-0031-1296847.
The aim of this study was to compare the extent and rate of absorption of two different carvedilol (CAS 72956-09-3) tablet formulations: 25 mg tablets, as the test formulation and the reference innovator product (25 mg tablets).
This study was designed as a single-dose, open-label, randomised, with a two-period and two-sequence crossover design, with blind determination of drug plasma concentration and a minimum 7-day washout period. Twenty-four healthy volunteers of both sexes were randomly assigned to treatment sequences. Carvedilol concentrations were determined in plasma samples obtained over a 24-h interval: baseline (pre-administration) and at 14 different times within the 24 h after administration. The analytical method, which used HPLC coupled with a MS/MS detector, was duly validated and the analytical assay was performed in compliance with Good Laboratory Practice (GLP). The limit of quantification (LOQ) was 0.50 ng/mL. Pharmacokinetic parameters representing the extent and/or rate of absorption (AUCinf, AUClast, and Cmax) were obtained. As secondary objective the tolerability of both formulations was also evaluated.
The geometric mean of the test/reference formulations individual percent ratio was 98.14 % for AUCinf, 98.44 % for AUClast and 98.39 % for Cmax. The 90 % CI for the geometric mean of the individual ratio test/references formulations was 95.13 to 101.24 % for AUCinf, 95.23 to 101.76 % for AUClast, and 88.26 to 109.67 % for Cmax.
The 90 % CI values obtained for AUCinf, AUClast, and Cmax are within the interval proposed by the EMEA/CPMP and the FDA as bioequivalence acceptance criteria, and consequently it can be conclude that the test formulation is bioequivalent with the reference formulation both in terms of rate and extent of absorption after single dose administration. The results from a previous pilot study allowed an optimal design for this trial.
本研究旨在比较两种不同的卡维地洛（CAS 72956 - 09 - 3）片剂制剂的吸收程度和速率：25毫克片剂作为试验制剂，以及参比创新产品（25毫克片剂）。
本研究设计为单剂量、开放标签、随机、两周期两序列交叉设计，采用盲法测定药物血浆浓度，洗脱期至少7天。24名男女健康志愿者被随机分配到治疗序列。在给药后24小时内的14个不同时间点以及基线（给药前）采集血浆样本，测定卡维地洛浓度。采用高效液相色谱 - 串联质谱检测器的分析方法经过充分验证，分析测定按照良好实验室规范（GLP）进行。定量限（LOQ）为0.50纳克/毫升。获得了代表吸收程度和/或速率的药代动力学参数（AUCinf、AUClast和Cmax）。作为次要目的，还评估了两种制剂的耐受性。
试验制剂/参比制剂个体百分比比值的几何均值，AUCinf为98.14%，AUClast为98.44%，Cmax为98.39%。试验制剂/参比制剂个体比值几何均值的90%置信区间，AUCinf为95.13%至101.24%，AUClast为95.23%至101.76%，Cmax为88.26%至109.67%。
AUCinf、AUClast和Cmax获得的90%置信区间值在欧洲药品管理局/人用药品委员会（EMEA/CPMP）和美国食品药品监督管理局（FDA）提出的生物等效性接受标准范围内，因此可以得出结论，试验制剂在单剂量给药后的吸收速率和程度方面与参比制剂具有生物等效性。先前一项预试验的结果为此项试验提供了优化设计。
