健康志愿者中阿德福韦酯的单、多剂量药动学研究

Study on pharmacokinetics of single and multi-dose of oral adefovir dipivoxil tablets in healthy volunteers

目的：评估健康志愿者单次、多次口服阿德福韦酯片剂(ADV)的药动学。方法：共27名健康志愿者入选本研究,其中12名受试者采用交叉、随机、开放和拉丁方设计的方法,分别单次给予ADV 5,10,30 mg,进行单剂量药动学研究。另15名受试者(其中3名服用安慰剂)采用随机、双盲、安慰剂对照设计方法,口服ADV 10 mg,qd×6 d,研究多剂量药动学。结果：口服ADV 5,10,30 mg,t_(max)的中位数为1．00,0．65,0．88 h；t_(1/2)为(10±5),(9．2±2．8),(8．4±1．4)h；c_(max)为(11±4),(25±8),(76±23)μg·L^(-1)；AUC_(0～t)为(143±52),(235±82),(715±268)μg·h·L^(-1)。单次和多次口服ADV 10 mg达稳态后,t_(max)的中位数为1．00,0．88 h；t_(1/2)为(8．1±2．0),(9．7±2．8)h；c_(max)为(22±5),(27±7)μg·L^(-1)；AUC_(0～t)为(206±53),(289±91)μg·h·L^(-1)。结论：ADV吸收迅速,c_(max)和AUC_(0～t)的增加与剂量呈正相关,连续给药未见蓄积,血药浓度d 4达稳态,主要经肾脏排泄。

AIM： To investigate the pharmacokinetics of adefovir dipivoxil （ADV） with a single and multiple-dose oral administration in Chinese healthy volunteers. METHODS： All together 27 healthy volunteers were enrolled. A randomized, cross-over study was performed in 12 volunteers with three phases separated by a washout period of 1 wk. The drug concentrations of plasma sample from them after taking ADV tablets 5, 10, 30 nag were determined and the pharmacokinetic parameters were calculated. On the other hand, another 15 selected healthy volunteers were administrated ADV 10 mg or placebo （the ratio of ADV and placebo was 4 ： 1 ） once a day for 6 d. The plasma concentrations after d 1 and d 7 and urine concentrations in 48 h after d 1 of ADV were determined by LC/MS/MS and the pharmacokinetic parameters were calculated by WinNonLin. RESULTS： The main pharmacokinetic parameters of ADV after oral 5, 10, 30 mg showed as follow, median of t.,=were 1.00, 0.65 and 0.88h; t1/2 were （10±5）, （9.2±2.8） and （8.5± 1.4） h; cmax were （11 ±4）, （25 ± 8） and （76 ± 23）μg·L^-1; AUC0-1 were （143 ± 52）, （235 ± 82） and （715 ± 268） μg·L^-1. The main pharmacokinetic parameters of ADV after a single oral dose （ 10 mg） and multiple-dose were as follow, median of tmax were 1.00 and 0.88 h; t1/2were （8.1 ±2.0 ） and （9.7±2.8） h; cmax were （22±5） and （27 ± 7） μg·L^-1; AUC0-1 were （206 ± 53） and （289 ± 91） μg·L^-1 CONCLUSION： ADV can be absorbed rapidly and the increase of cmax and A UC0-1 are directly in positive correlation with that of ADV doses; without accumulation in plasma after multiple-dose of administration, reaching stabilization at d 4, and excreting mainly through kidney.