替比夫定的药代动力学研究

目的评价中国健康志愿者单次口服不同剂量替比夫定的药代动力学特征以及多次给药后的稳态血浆药代动力学。方法42名年龄在18～40岁的健康志愿者,男32名,女10名,随机分配到200、400、600、800mg 4个剂量组。其中600mg剂量组受试者接受单剂量和多剂量的研究。多剂量每日给药,持续8d。采用HPLC-MS/MS法测定给药前和给药后不同时间替比夫定的主血浆、尿液药物浓度,并据此计算药代动力学参数。结果在单次口服200、400、600、800mg片剂后,受试者的达峰时间分别为2．50、2．00、2．00h和2．50h；半衰期的平均值分别为(43．3±15．2)h、(49．1±14．4)h、(39．4±12．1)h和(46．7±20．8)h；血药达峰浓度平均值分别为(1 753．2±389．0)ng/ml、(2 586．7±871．4)ng/ml、(3 703．6±1 219．0)ng/ml和(3 454．6±953．9)ng/ml；曲线下面积的平均值分别为(12 843．2±2 925．6)ng·h ~(1·)ml~1、(22 948．9±5 721．0)ng·~(1·)ml~1、(26 440．5±8 938．1)ng·h ~(1·)ml~1以及(28 820．9±7 912．9)ng·h ~(1·)ml~1；血浆清除率(600mg)为(6 545．6±1 504．4)ml/h；多次给药后的稳态药代动力学研究结果显示,在600mg/d的给药剂量下,连续给药8d后,平均稳态药时曲线下面积为(26 123．9±7 196．3)ng·h ~(1·)ml~1,平均血药浓度为(1 088．5±299．8)ng/ml,血药达峰浓度和曲线下面积蓄积囚子分别为1．02±0．21和1．23±0．26。结论受试者口服替比夫定以后,吸收较为迅速,给药后的2～3h即达到峰值。在200mg至800mg剂量范围内,血浆中替比夫定的药代动力学参数均呈现出一定的规律。替比夫定在受试者体内有轻微蓄积。

Study on the pharmacokinetic profile of telbivudine

OBJECTIVE: To evaluate the pharmacokinetic profile of telbivudine in healthy Chinese subjects after oral administration of single and multiple doses. METHODS: Forty-two healthy adult male and female subjects 18-40 years of age were randomized into four telbivudine dosing groups of 200 mg, 400 mg, 600 mg and 800 mg. Subjects in the 600 mg group received both a single dose and once daily multiple doses for 8 consecutive days. Telbivudine concentrations in plasma and urine samples collected at different time points before and after the drug administration were measured using HPLC-MS/MS. Pharmacokinetic parameters were calculated by using the non-compartmental approach. RESULTS: After a single dose of 200 mg, 400 mg, 600 mg and 800 mg, tmax (median) were 2.50, 2.00, 2.00 and 2.50 hours respectively; t1/2 were (43.3 +/- 15.2) h, (49.1 +/- 14.4) h, (39.4 +/- 12.1) h and (46.7 +/- 20.8) h respectively; Cmax were (1,753.2 +/- 389.0) ng/ml, (2,586.7 +/- 871.4) ng/ml, (3,703.6 +/- 1,219.0) ng/ml and (3454.6 +/- 953.9) ng/ml respectively; AUC(0-infinity) were (12,843.2 +/- 2,925.6) ng.h(-1).ml(-1), (22,948.9 +/- 5,721.0) ng.h(-1)/ml(-1), (26,440.5 +/- 8,938.1) ng.h(-1).ml(-1) and (28, 820.9 +/- 7 912.9) ng.h(-1).ml(-1) respectively, and CL(R) (600 mg) was (6,545.6 +/- 1 504.4) ml/h. The AUCss from multiple doses was (1,088.5 +/- 299.8) ng/ml; Cmax and AUC accumulation ratio were 1.02 +/- 0.21 and 1.23 +/- 0.26 respectively, which implicated moderated accumulation. CONCLUSION: Pharmacokinetic parameters of telbivudine in Chinese healthy subjects were determined.