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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 study the pharmacokinetics of entecavir maleate tablets in healthy volunteers. Methods: A single-dose pharmacokinetic test was conducted with entecavir maleate at low (0.25 mg), medium (0.5 mg) and high (1.0 mg) doses using an open-label, randomized trial design. Multiple doses and steady-state tests were performed at intermediate doses for 12 semi-healthy subjects in each dose group, compared with single and steady-state trials of 0.5 mg dose of entecavir (commercially available). Liquid chromatography-tandem mass spectrometry (LC-MS / MS) was used to determine the concentration of entecavir in plasma and urine. Pharmacokinetic parameters were calculated using the DAS 2.0 program. Results: The single oral dose of entecavir maleate showed a positive correlation with the dose of Cmax and AUC, but Tmax and t1 / 2 were not significantly affected by the dose change. The mean urinary cumulative excretion rate at 48 h was (40.0 ± 10.7)%. The drug accumulation index reached about 2 times when it was administered in multiple steady state. There was no significant difference in the main pharmacokinetic parameters between male and female subjects. There was no significant difference in the main pharmacokinetic parameters of entecavir maleate tablets and buprofezin. Conclusion: The established LC-MS / MS method for the determination of entecavir in plasma and urine is sensitive and meets the requirements of clinical biological samples analysis. The pharmacokinetics of oral entecavir maleate has linear pharmacokinetic characteristics in healthy human Consistent with Bo Road set.