Jullien Vincent, Tréluyer Jean-Marc, Rey Elisabeth, Jaffray Patrick, Krivine Anne, Moachon Laurence, Lillo-Le Louet Agnès, Lescoat Anne, Dupin Nicolas, Salmon Dominique, Pons Gérard, Urien Saïk
Service de Pharmacologie Clinique, Hôpital Cochin-Saint-Vincent-de-Paul, 74-82 Avenue Denfert-Rochereau, 75674 Paris Cedex 14, France.
Antimicrob Agents Chemother. 2005 Aug;49(8):3361-6. doi: 10.1128/AAC.49.8.3361-3366.2005.
The influence of renal function on tenofovir pharmacokinetics was investigated in 193 human immunodeficiency virus (HIV)-infected patients by the use of a population approach performed with the nonlinear mixed effects modeling program NONMEM. Tenofovir pharmacokinetics was well described by a two-compartment open model in which the absorption and the distribution rate constants are equal. Typical population estimates of apparent central distribution volume (V(c)/F), peripheral distribution volume (V(p)/F), intercompartmental clearance (Q/F), and plasma clearance (CL/F) were 297 +/- 28.5 [corrected] liters, 848 +/- 209 [corrected] liters, 80 +/- 15 [corrected] liters/h and 50.5 +/- 3.1 [corrected] liters/h, respectively. Apparent plasma clearance was related to body weight/serum creatinine ratio (BW/S(CR)) and to the existence of a tubular dysfunction. Concomitant treatment with lopinavir/ritonavir was found to decrease tenofovir clearance. Individual Bayesian estimates of CL/F were used to calculate the tenofovir area under the concentration-time curve from time zero to 24 h (AUC(0-24)). In patients without tubular dysfunction, AUC(0-24) values markedly decreased from 6.7 to 1.4 mg . h/liter for BW/S(CR) increasing from 0.44 to 1.73. The relevance of a dosage adjustment based on BW/S(CR) should be further evaluated.
采用非线性混合效应建模程序NONMEM进行群体分析，在193例人类免疫缺陷病毒（HIV）感染患者中研究了肾功能对替诺福韦药代动力学的影响。替诺福韦药代动力学通过一个双室开放模型得到很好的描述，其中吸收速率常数和分布速率常数相等。表观中央分布容积（V(c)/F）、外周分布容积（V(p)/F）、室间清除率（Q/F）和血浆清除率（CL/F）的典型群体估计值分别为297±28.5[校正后]升、848±209[校正后]升、80±15[校正后]升/小时和50.5±3.1[校正后]升/小时。表观血浆清除率与体重/血清肌酐比值（BW/S(CR)）以及肾小管功能障碍的存在有关。发现洛匹那韦/利托那韦联合治疗会降低替诺福韦清除率。使用CL/F的个体贝叶斯估计值来计算替诺福韦从时间零到24小时的浓度-时间曲线下面积（AUC(0-24)）。在没有肾小管功能障碍的患者中，随着BW/S(CR)从0.44增加到1.73，AUC(0-24)值从6.7显著降低至1.4毫克·小时/升。基于BW/S(CR)进行剂量调整的相关性应进一步评估。
