Pharmacokinetics of drugs can be affected by physiologic changes during pregnancy. Our aim was to assess the influence of covariates on tenofovir (TFV) pharmacokinetics in pregnant and postpartum women receiving tenofovir disoproxil fumarate (TDF). Population pharmacokinetic parameter estimates and the influence of covariates were assessed using nonlinear mixed-effects modeling (NONMEM 7.4). Forty-six women had intensive pharmacokinetic evaluations during the second and third trimesters of pregnancy, with another evaluation postpartum. A two-compartment pharmacokinetic model with allometric scaling for body weight and first-order absorption best described the tenofovir plasma concentration data. Apparent oral clearance (CL/F) and volume of distribution at steady state (V_ss/F) were increased during pregnancy. Weight, serum creatinine (SCr), pregnancy, albumin, and age were associated with TFV CL/F during univariate assessment, but in the multivariate analysis, changes in CL/F and V_ss/F were only associated with increased body weight and enhanced renal function. Due to greater weight and lower SCr during pregnancy, CL/F was 28% higher during pregnancy than postpartum. In the final model, CL/F (liters per hour) was described as 2.07 × (SCr/0.6)^0.65 × weight^0.75, with a low between-subject variability (BSV) of 24%. The probability of target attainment (proportion exceeding area under the concentration-time curve of >1.99 μg·h/ml, the 10th percentile of average TFV exposure for nonpregnant historical controls) was 68%, 80%, 87%, and 93% above the target with 300 mg, 350 mg, 400 mg, and 450 mg of TDF, respectively, during pregnancy and 88%, 92%, 96%, and 98% above the target with same doses in postpartum women. Dose adjustment of TDF during pregnancy is not generally warranted, but any modification should be based on weight and renal function. (This study has been registered at ClinicalTrials.gov under identifier NCT00042289.)

中文翻译：

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使用富马酸替诺福韦酯在孕妇和产后妇女中的群体药代动力学

药物的药代动力学会受到孕期生理变化的影响。我们的目的是评估协变量对接受富马酸替诺福韦酯 (TDF) 的孕妇和产后妇女替诺福韦 (TFV) 药代动力学的影响。使用非线性混合效应模型 (NONMEM 7.4) 评估群体药代动力学参数估计和协变量的影响。46 名妇女在妊娠中期和晚期进行了密集的药代动力学评估，产后进行了另一次评估。具有异速缩放体重和一级吸收的两室药代动力学模型最好地描述了替诺福韦血浆浓度数据。表观口服清除率 (CL/F) 和稳态分布容积 ( V _ss/F) 在怀孕期间增加。在单变量评估中，体重、血清肌酐 (SCr)、妊娠、白蛋白和年龄与 TFV CL/F 相关，但在多变量分析中，CL/F 和V _ss /F 的变化仅与体重增加和增强肾功能。由于怀孕期间体重较大且 SCr 较低，因此怀孕期间的 CL/F 比产后高 28%。在最终模型中，CL/F（升/小时）被描述为 2.07 × (SCr/0.6) ^0.65 × 重量^0.75，具有 24% 的低受试者间变异性 (BSV)。达到目标的概率（超过浓度-时间曲线下面积 >1.99 μg·h/ml，非妊娠历史对照平均 TFV 暴露的第 10 个百分位）的概率分别为 68%、80%、87% 和 93% 以上在怀孕期间分别使用 300 毫克、350 毫克、400 毫克和 450 毫克的 TDF，产后妇女在相同剂量下分别比目标高 88%、92%、96% 和 98%。通常不需要在怀孕期间调整 TDF 的剂量，但任何调整都应基于体重和肾功能。（本研究已在 ClinicalTrials.gov 上注册，标识符为 NCT00042289。）