Population Pharmacokinetics of Tenofovir and Tenofovir-Diphosphate in Healthy Women
Population Pharmacokinetics of Tenofovir and Tenofovir-Diphosphate in Healthy Women
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DOI：
10.1002/jcph.461
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发表时间：
2015-06-01
影响因子：
2.9
通讯作者：
Chaturvedula, Ayyappa
中科院分区：
文献类型：
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作者：
Burns, Rebecca N.;Hendrix, Craig W.;Chaturvedula, Ayyappa
该分析的目的是建立和验证来自MTN-001临床试验的健康女性志愿者外周血单个核细胞（PBMC）血浆替诺福韦（TFV）浓度和替诺福韦二磷酸（TFV- dp）浓度的群体药代动力学模型，这是一项口服富马酸替诺福韦二oproxil 300 mg片剂、TFV 1%阴道凝胶或两者同时进行的开放标签3-way交叉研究。采用具有吸收滞后时间的2室一级吸收/消除模型来描述TFV的药代动力学。TFV通过一阶摄取和一阶消除与PBMC的TFV- dp相关联。通过明确模拟前一天剂量的生物利用度参数，包括依从性调整，以解释不依从性。最终模型将体重作为影响中央室容积（V-c）的协变量，估计如下：吸收率常数（Ka） 9.79 h(-1)，吸收滞后时间0.5 h, V-c 385.71-2.16*(73-WT(kg))，表观TFV清除率56.7 L/h （(K20_K24)*V-c）。ttv - dp的半衰期为53.3小时。所有诊断图和自举置信区间均可接受。通过模拟与MTN-001口腔+阴道期和其他临床试验数据进行比较，对模型进行验证。与来自另一项临床试验的健康参与者数据相比，所得到的模型可以准确预测TFV和TFV- dp的处置。
The objective of this analysis was to develop and qualify a population pharmacokinetic model describing plasma tenofovir (TFV) concentrations and tenofovir-diphosphate (TFV-DP) concentrations in peripheral blood mononuclear cell (PBMC) in healthy women volunteers from the MTN-001 clinical trial, an open label 3-way crossover study of oral tenofovir disoproxil fumarate 300 mg tablet, TFV 1% vaginal gel, or both. TFV pharmacokinetics were best described by a 2-compartment, first-order absorption/elimination model with absorption lag time. TFV was linked to PBMC TFV-DP by first-order uptake with first-order elimination. An adherence adjustment was included to account for nonadherence by explicitly modeling a bioavailability parameter on the previous day's dose. The final model included weight as a covariate on central compartment volume (V-c) with estimates as follows: absorption rate constant (Ka) 9.79 h(-1), absorption lag time 0.5 hours, V-c 385.71-2.16*(73-WT(kg)), and apparent TFV clearance of 56.7 L/h ((K20_K24)*V-c). TFV-DP's half-life was 53.3 hours. All diagnostic plots and bootstrap confidence intervals were acceptable. Model validation was conducted using simulations compared to data from the MTN-001 oral+vaginal period and other clinical trial data. The resulting model closely predicted the disposition of TFV and TFV-DP when compared to healthy participant data from another clinical trial.