Neves Rita, Almeida Susana, Filipe Augusto, Spínola Ana Cristina Franco, Abolfathi Zohreh, Yritia Mercedes, Ortuño Jordi
Medical Department, Grupo Tecnimede, Prior Velho, Portugal.
Arzneimittelforschung. 2008;58(8):369-75. doi: 10.1055/s-0031-1296523.
The study was conducted in order to assess the bioequivalence of two film-coated formulations containing 100 mg of losartan (CAS 124750-99-8) and 12.5 mg of hydrochlorothiazide (CAS 58-93-5). Seventy-three healthy subjects were enrolled in a randomised, single-dose, open-label, two-way crossover study, with a minimum washout period of 7 days. A total of 21 blood samples were collected up to 36 h post-dosing. Losartan, losartan carboxy acid and hydrochlorothiazide levels were determined by liquid chromatography with tandem mass detection (lower limit of quantification: 1.01 ng/mL for hydrochlorothiazide, 2.02 ng/mL for losartan and 2.51 ng/mL for losartan carboxy acid). Pharmacokinetic parameters used for bioequivalence assessment (AUC(0-t) and Cmax as primary and AUC(0-inf) as secondary pharmacokinetic parameters) were determined from the losartan and hydrochlorothiazide concentration data using non-compartmental analysis. Data from losartan carboxy acid was reported and presented as supportive data. The 90% confidence intervals (obtained by ANOVA) for losartan were 97.05-118.48% for Cmax 100.76-106.10% for AUC(0-t) and 100.80-106.10% for AUC(0-inf) whereas for hydrochlorothiazide the 90% confidence intervals obtained were 103.94-115.33% for Cmax, 101.97-109.61% for AUC(0-t) and 101.77-109.02% for AUC(0-inf), and for losartan carboxy acid the intervals obtained were 98.31-107.82% for Cmax, 97.89-104.30% for AUC(0-t) and 98.06-104.30% for AUC(0-inf). All the 90% confidence intervals obtained for all the parameters assessed were within the predefined ranges (80-125%). Based on these results, it can be concluded that the evaluated formulations are bioequivalent in terms of rate and extent of absorption.
本研究旨在评估两种薄膜包衣制剂的生物等效性，这两种制剂分别含有100 mg氯沙坦（CAS 124750-99-8）和12.5 mg氢氯噻嗪（CAS 58-93-5）。73名健康受试者参与了一项随机、单剂量、开放标签、双向交叉研究，最短洗脱期为7天。给药后36小时内共采集21份血样。采用液相色谱-串联质谱检测法测定氯沙坦、氯沙坦羧酸和氢氯噻嗪的水平（定量下限：氢氯噻嗪为1.01 ng/mL，氯沙坦为2.02 ng/mL，氯沙坦羧酸为2.51 ng/mL）。用于生物等效性评估的药代动力学参数（以AUC(0-t)和Cmax作为主要参数，AUC(0-inf)作为次要药代动力学参数）通过非房室分析从氯沙坦和氢氯噻嗪浓度数据中确定。氯沙坦羧酸的数据作为支持性数据进行报告和呈现。氯沙坦的90%置信区间（通过方差分析获得），Cmax为97.05-118.48%，AUC(0-t)为100.76-106.10%，AUC(0-inf)为100.80-106.10%；而氢氯噻嗪的90%置信区间，Cmax为103.94-115.33%，AUC(0-t)为101.97-109.61%，AUC(0-inf)为101.77-109.02%；氯沙坦羧酸的区间，Cmax为98.31-107.82%，AUC(0-t)为97.89-104.30%，AUC(0-inf)为98.06-104.30%。所有评估参数获得的90%置信区间均在预定义范围内（80-125%）。基于这些结果，可以得出结论，所评估的制剂在吸收速率和程度方面具有生物等效性。
