Neves Rita, Almeida Susana, Filipe Augusto, Spinola Ana Cristina Franco, Abolfathi Zohreh, Lévesque Ann, Ortuño Jordi, Torns Alex
Medical Department, Grupo Tecnimede, Sintra, Portugal.
Arzneimittelforschung. 2010;60(5):273-81. doi: 10.1055/s-0031-1296285.
These studies were conducted in order to assess the bioequivalence of two film-coated formulations containing 250 mg and 1000 mg of valacyclovir (INN: valaciclovir; CAS 124832-26-4), which is the L-valyl ester and a pro-drug of the antiviral drug acyclovir (INN: aciclovir). In the study with valacyclovir 250 mg, 36 healthy subjects were enrolled in a randomized, single-dose, open-label, 2-way crossover study, with a washout period of 10 days. In the study with valacyclovir 1000 mg, 46 healthy subjects were enrolled in a randomized, single-dose, open-label, 2-way crossover study, with a washout period of 7 days. Plasma samples were collected up to 36 h postdose for both studies. Valacyclovir levels were determined by liquid chromatography with tandem mass detection (ie, the LC/MS/MS method) (lower limit of quantification: 0.50 ng/ mL for valacyclovir and 9.93 ng/mL for acyclovir for the 250 mg study and 1.00 ng/mL for valacyclovir and 20.00 ng/ mL for acyclovir for the 1000 mg study). Pharmacokinetic parameters used for bioequivalence assessment were the area under the concentration-time curve from time zero to time of last non-zero concentration (AUC(0-t)) and from time zero to infinity (AUC(0-inf) and maximum observed concentration (C(max)). These parameters were determined from the valacyclovir concentration data using non-compartmental analysis. In the tained by analysis of variance (ANOVA) for valacyclovir were 107.54-124.26% for C(max), 95.45-103.46% for AUC(0-Inf) and 95.53-103.63% for AUC(0-t) whereas for acyclovir the 90% confidence intervals obtained were 103.19-117.02% for C(max), 99.61-106.92% for AUC(0-Inf) and 99.58-106.94% for AUC(0-t). In the study with valacyclovir 1000 mg formulations, the 90% confidence intervals obtained for valacyclovir were 93.20-107.35% for C(max), 90.87-96.27% for AUC(0-inf) and 90.87-96.27% for AUC(0-t) whereas for acyclovir the 90% CIs obtained were 95.98-104.94% for C(max), 97.13-103.94% for AUC(0-inf) and 97.14-104.09% for AUC(0-t). All the 90% confidence intervals obtained for all the parameters assessed were within the predefined range (80-125%). Based on these results, it can be concluded that the evaluated formulations are bioequivalent in terms of rate and extent of absorption.
进行这些研究是为了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250毫克和1000毫克伐昔洛韦（国际非专利药品名称：valaciclovir；化学物质登记号124832 - 26 - 4），它是抗病毒药物阿昔洛韦（国际非专利药品名称：aciclovir）的L - 缬氨酸酯和前体药物。在伐昔洛韦250毫克的研究中，36名健康受试者参与了一项随机、单剂量、开放标签的双交叉研究，洗脱期为10天。在伐昔洛韦1000毫克的研究中，46名健康受试者参与了一项随机、单剂量、开放标签的双交叉研究，洗脱期为7天。两项研究均在给药后长达36小时采集血浆样本。伐昔洛韦水平通过液相色谱 - 串联质谱检测法（即LC/MS/MS方法）测定（定量下限：2五百毫克研究中伐昔洛韦为0.50纳克/毫升，阿昔洛韦为9.93纳克/毫升；1000毫克研究中伐昔洛韦为1.00纳克/毫升，阿昔洛韦为20.00纳克/毫升）。用于生物等效性评估的药代动力学参数是从零时间到最后一个非零浓度时间的浓度 - 时间曲线下面积（AUC(0 - t)）、从零时间到无穷大的浓度 - 时间曲线下面积（AUC(0 - inf)）以及最大观测浓度（C(max)）。这些参数通过非房室分析从伐昔洛韦浓度数据中确定。对于伐昔洛韦，通过方差分析（ANOVA）获得的C(max)的90%置信区间为107.54 - 124.26%，AUC(0 - Inf)为95.45 - 103.46%，AUC(0 - t)为95.53 - 103.63%；而对于阿昔洛韦，获得的90%置信区间为C(max)为103.19 - 117.02%，AUC(0 - Inf)为99.61 - 106.92%，AUC(0 - t)为99.58 - 106.94%。在伐昔洛韦1000毫克制剂的研究中，伐昔洛韦获得的90%置信区间为C(max)为93.20 - 107.35%，AUC(0 - inf)为90.87 - 96.27%，AUC(0 - t)为90.87 - 96.27%；而对于阿昔洛韦，获得的90%置信区间为C(max)为95.98 - 104.94%，AUC(0 - inf)为97.13 - 103.94%，AUC(0 - t)为97.14 - 10,4.,09%。评估的所有参数获得的所有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。
