马来酸恩替卡韦片的健康人体药动学

Pharmacokinetics of entecavir maleate tablets in healthy Chinese volunteers

目的:研究马来酸恩替卡韦片在健康人体内的药动学。方法:采用开放、随机试验设计方案,进行马来酸恩替卡韦片以恩替卡韦计低(0.25 mg)、中(0.5 mg)、高(1.0 mg)3种剂量水平的单剂量药动学试验,并对中间剂量进行多次给药及稳态试验,每个剂量组12名男女各半健康受试者;并与市售恩替卡韦片(博路定)0.5 mg剂量的单次和稳态试验进行比较。液相色谱-串联质谱法(LC-MS/MS)测定血浆和尿液中恩替卡韦的浓度。应用DAS 2.0程序计算药动学参数。结果:单剂量口服马来酸恩替卡韦片,血浆Cmax和AUC与剂量成正比例关系,Tmax和t1/2基本不受剂量变化的显著影响;48 h的平均尿液累积排泄率总平均为(40.0±10.7)%。多次连续给药达稳态时药物蓄积指数约为2倍。男女受试者的主要药动学参数无明显差异。马来酸恩替卡韦片与博路定的主要药动学参数无显著性差异。结论:建立血浆和尿液中恩替卡韦的LC-MS/MS测定法专属灵敏,满足临床生物样本分析的要求;口服马来酸恩替卡韦片在健康人体内的药动学具有线性药动学特征,并与博路定的一致。

Objective： To investigate the pharmacokinetics of entecavir maleate tablets in healthy Chinese volunteers. Methods： In a randomized study design, single oral dose of entecavir maleate tablets equivalent to 0.25, 0.5 or 1.0 mg entecavir was given to each of 12 healthy Chinese volunteers of equal genders after an overnight fast. The single and steady-state after multiple 0.5 mg doses of entecavir maleate tablets were also investigated and compared with the entecavir tablets （Baraclude）. The plasma and urine concentrations of entecavir were determined by a validated LC-MS/MS method. The pharmacokinetic parameters were evaluated by DAS 2.0 software. Results： Both plasma Cmax and AUC of entecavir were increased proportionally with the oral doses while the T and t1/2 were remained without significant variation, respectively. The cumulative percent excreted amounts through urine in 48 h after administration were all similar with a total average of （40.0 ± 10.7 ） %. The cumulative factor of AUC at steady-state after multiple doses was about 2. No significant differences of the pharmacokinetics were found between entecavir maleate tablets and Baraclude, and there were no gender differences as well. Conclusion： The established LC-MS/MS method for plasma and urine entecavir determination is sensitive, selective and feasible for the pharmacokinetic study. Linear pharmacokinetics is observed for the entecavir maleate tablets as the same as that of Baraclude.