UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, 27599-7569, USA.
Clin Pharmacokinet. 2012 Dec;51(12):809-22. doi: 10.1007/s40262-012-0012-y.
A previously published study of antiretroviral pharmacokinetics in the female genital tract of HIV-infected women demonstrated differing degrees of female genital tract penetration among antiretrovirals. These blood plasma (BP) and cervicovaginal fluid (CVF) data were co-modelled for four antiretrovirals with varying CVF exposures.
Six paired BP and CVF samples were collected over 24 h, and antiretroviral concentrations determined using validated liquid chromatography (LC) with UV detection or LC-mass spectrometry analytical methods. For each antiretroviral, a BP model was fit using Bayesian estimation (ADAPT5), followed by addition of a CVF model. The final model was chosen based on graphical and statistical output, and then non-linear mixed-effects modelling using S-ADAPT was performed. Population mean parameters and their variability are reported. Model-predicated area under the concentration-time curve during the dosing interval (AUC(τ)) and exposure ratios of CVF AUC(τ):BP AUC(τ) were calculated for each drug.
The base model uses first-order absorption with a lag time, a two-compartment model, and a series of transit compartments that transfer the drug from BP to CVF. Protein-unbound drug transfers into CVF for efavirenz and atazanavir; total drug transfers for lamivudine and tenofovir. CVF follows a one-compartment model for efavirenz and atazanavir, and a two-compartment model for lamivudine and tenofovir. As expected, inter-individual variability was high. Model-predicted CVF AUC(τ):BP AUC(τ) ratios are consistent with published results.
This is the first pharmacokinetic modelling of antiretroviral disposition in BP and CVF. These models will be further refined with tissue data, and used in clinical trials simulations to inform future studies of HIV pre-exposure prophylaxis in women.
之前有一项关于 HIV 感染女性生殖道内抗逆转录病毒药代动力学的研究，结果表明不同的抗逆转录病毒药物在女性生殖道内的穿透程度不同。本研究采用液质联用（LC-MS）和紫外检测（LC-UV）法检测 6 对 HIV 感染女性的 24 小时血药浓度和阴道分泌液浓度，对 4 种具有不同阴道分泌液浓度的抗逆转录病毒药物进行了血药浓度和阴道分泌液浓度的合并模型分析。采用贝叶斯估计（ADAPT5）建立每个药物的血药浓度模型，然后加入阴道分泌液模型。根据图形和统计输出选择最终模型，然后采用 S-ADAPT 进行非线性混合效应模型分析。报告群体均值参数及其变异性。计算每个药物的给药间隔时间内的浓度-时间曲线下面积（AUC（τ））和阴道分泌液 AUC（τ）/血药 AUC（τ）比值。
基础模型采用一级吸收，具有时滞、双室模型和一系列转移室，将药物从血药转移到阴道分泌液。对于依非韦伦和阿扎那韦，无蛋白结合药物向阴道分泌液转移；对于拉米夫定和替诺福韦，总药物转移。对于依非韦伦和阿扎那韦，阴道分泌液采用一室模型，对于拉米夫定和替诺福韦，采用二室模型。与预期一致，个体间变异性很高。模型预测的阴道分泌液 AUC（τ）/血药 AUC（τ）比值与已发表的结果一致。
这是首次对血药浓度和阴道分泌液中的抗逆转录病毒药物分布进行药代动力学建模。这些模型将进一步与组织数据相结合，并用于临床试验模拟，为未来的女性 HIV 暴露前预防研究提供信息。
