Panhard X, Goujard C, Legrand M, Taburet A M, Diquet B, Mentré F
INSERM U738, Department of Epidemiology, Biostatistics and Clinical research, AP-HP, Bichat University Hospital, Paris, France.
Br J Clin Pharmacol. 2005 Oct;60(4):390-403. doi: 10.1111/j.1365-2125.2005.02456.x.
To describe the pharmacokinetics of nelfinavir and its main metabolite M8 in HIV-infected patients with a sustained virological response, to characterize the effect of covariates and to estimate inter- and intra-individual variability in the pharmacokinetics.
Three hundred and twenty concentrations of both nelfinavir and M8 were measured in 46 patients enrolled in the COPHAR 1-ANRS 102 study. Blood samples were taken at a first visit (one sample before drug administration and four samples at fixed times after) and at a second visit 1 to 3 months later (one before and one 3 h after drug administration). The data from both visits on nelfinavir and M8 were modelled jointly in all patients using a population approach.
A one-compartment model with first-order absorption and elimination best described nelfinavir data, with an additional compartment incorporating a first order rate-constant describing the metabolism of the drug to M8. For nelfinavir, the apparent volume of distribution (V/F ) (95% confidence interval for the mean), was 309 l (185, 516), the absorption rate constant (k(a)) was 0.4 h(-1) (0.2, 0.8), and the apparent clearance (CL/F ) was 37.3 l h(-1) (32, 44). For M8, V(m) /(Fk(m)) and CL(m)/(Fk(m)) were 866 l h(-1) (351, 2161) and 1670 l (965, 2894), respectively. The interindividual variabilities were 34.9%, 34.3% and 62.2% for V/F, CL/F and CL(m)/(Fk(m)), respectively. The interoccasion variability was 27.8% for CL/F. The mean half-lives were 05.38 h and 00.44 h for nelfinavir and M8, respectively. Significant but opposite effects of comedication with zidovudine were found on nelfinavir CL/F and M8 CL(m)/(Fk(m)), but they were not considered to be clinically relevant.
A joint model was found to describe adequately nelfinavir and M8 concentrations and was used to estimate pharmacokinetic parameters for M8. The model can be used to build reference pharmacokinetic profiles for therapeutic drug monitoring of the drug.
描述奈非那韦及其主要代谢产物M8在病毒学应答持续的HIV感染患者中的药代动力学，表征协变量的影响并估计药代动力学的个体间和个体内变异性。
在参与COPHAR 1-ANRS 102研究的46例患者中测量了320个奈非那韦和M8的浓度。在首次就诊时（给药前1个样本，给药后固定时间4个样本）以及1至3个月后的第二次就诊时（给药前1个样本，给药后3小时1个样本）采集血样。使用群体方法对所有患者两次就诊时奈非那韦和M8的数据进行联合建模。
具有一级吸收和消除的单室模型最能描述奈非那韦数据，另有一个室纳入了描述药物代谢为M8的一级速率常数。对于奈非那韦，分布表观容积（V/F）（均值的95%置信区间）为309升（185, 516），吸收速率常数（k(a)）为0.4 h(-1)（0.2, 0.8），表观清除率（CL/F）为37.3升/小时（32, 44）。对于M8，V(m) /(Fk(m))和CL(m)/(Fk(m))分别为866升/小时（351, 2161）和1670升（965, 2894）。V/F、CL/F和CL(m)/(Fk(m))的个体间变异性分别为34.9%、34.3%和62.2%。CL/F的两次就诊间变异性为27.8%。奈非那韦和M8的平均半衰期分别为5.38小时和0.44小时。发现齐多夫定合并用药对奈非那韦CL/F和M8 CL(m)/(Fk(m))有显著但相反的影响，但认为它们不具有临床相关性。
发现一个联合模型能充分描述奈非那韦和M8的浓度，并用于估计M8的药代动力学参数。该模型可用于建立该药物治疗药物监测的参考药代动力学曲线。
