Plasma and Intracellular Population Pharmacokinetic Analysis of Tenofovir in HIV-1-Infected Patients
Plasma and Intracellular Population Pharmacokinetic Analysis of Tenofovir in HIV-1-Infected Patients
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DOI：
10.1128/aac.05317-11
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发表时间：
2011-11-01
影响因子：
4.9
通讯作者：
Fletcher, Courtney V.
中科院分区：
文献类型：
--
作者：
Baheti, Gautam;Kiser, Jennifer J.;Fletcher, Courtney V.
富马酸替诺福韦酯（TDF）剂量、替诺福韦（TFV）血浆浓度和细胞内TFV二磷酸盐（TFV-DP）浓度之间的关系尚不清楚。我们的目的是表征TFV和TFV-DP的关系。数据汇总自两项针对接受稳定抗逆转录病毒治疗的艾滋病毒感染者（n = 55）的研究。采用经验证的液相色谱/串联质谱法（LC/MS/MS）测定TFV和TFV-DP。使用非线性混合效应模型（NONMEM 7）建立群体模型，并探索协变量对TFV的影响。采用序贯分析方法。具有一级吸收的二室模型最能描述TFV PK（FOCEI）。间接刺激反应模型最好地描述了TFV-DP，其中TFV-DP的形成由血浆TFV浓度驱动。最终血浆群体估计值如下：吸收速率常数，1.03 h（-1）;表观清除率（CL/F），42 L/h（33.5%个体间变异性[IIV]）;室间清除率，181 L/h;表观中央分布容积（Vc/F），273 L表观外周分布容积（Vp/F）为440 L（46.5% IIV）。肌酐清除率是CL/F和Vc/F的最显著协变量。CL/F与Vc/F的相关系数为0.553。TFV-DP的间接响应模型分别估算了300 fmol/10（6）个细胞（82% IIV）、100 ng/ml（106% IIV）和0.008 h（-1）的最大细胞内浓度（E（max））、产生50% E（max）的TFV浓度（EC（50））和细胞内消除速率常数（k（out））。估计的k（out）给出了87小时的TFV-DP半衰期。预测检查评估表明，令人满意的模型性能。该模型将TFV-DP的形成与血浆TFV浓度联系起来，应有助于对TFV临床药理学进行更深入的研究。
The relationships among the dose of tenofovir disoproxil fumarate (TDF), tenofovir (TFV) plasma concentrations, and intracellular TFV diphosphate (TFV-DP) concentrations are poorly understood. Our objective was to characterize TFV and TFV-DP relationships. Data were pooled from two studies in HIV-infected persons (n = 55) on stable antiretroviral therapy. TFV and TFV-DP were measured with validated liquid chromatography/tandem mass spectrometry (LC/MS/MS) methods. Nonlinear mixed effects modeling (NONMEM 7) was used to develop the population model and explore the influence of covariates on TFV. A sequential analysis approach was utilized. A two-compartment model with first-order absorption best described TFV PK (FOCEI). An indirect stimulation of response model best described TFV-DP, where formation of TFV-DP was driven by plasma TFV concentration. Final plasma population estimates were as follows: absorption rate constant, 1.03 h(-1); apparent clearance (CL/F), 42 liters/h (33.5% interindividual variability [IIV]); intercompartment clearance, 181 liters/h; apparent central distribution volume (Vc/F), 273 liters (64.8% IIV); and apparent peripheral distribution volume (Vp/F), 440 liters (46.5% IIV). Creatinine clearance was the most significant covariate on CL/F and Vc/F. The correlation between CL/F and Vc/F was 0.553. The indirect response model for TFV-DP resulted in estimates of the maximal intracellular concentration (E(max)), the TFV concentration producing 50% of E(max) (EC(50)), and the intracellular elimination rate constant (k(out)) of 300 fmol/10(6) cells (82% IIV), 100 ng/ml (106% IIV), and 0.008 h(-1), respectively. The estimated k(out) gave an 87-h TFV-DP half-life. A predictive check assessment indicated satisfactory model performance. This model links formation of TFV-DP with plasma TFV concentrations and should facilitate more informed investigations of TFV clinical pharmacology.