Department of Biomedical Engineering, Duke University, Durham, North Carolina, USA.
Department of Obstetrics and Gynecology, Duke University, Durham, North Carolina, USA.
Sci Rep. 2019 Jan 14;9(1):82. doi: 10.1038/s41598-018-36004-z.
Microbicide pharmacokinetic (PK) studies typically sample drug in luminal fluid, mucosal tissue, and blood. Blood measurements can be conducted most frequently, serially within subjects. Antiretroviral drugs, however, act against HIV in mucosal tissue/cells. We computationally modeled the extent measurements in blood can predict concentrations in tissue, focusing on the antiretroviral drug tenofovir delivered by a vaginal gel. Deterministic PK models input host and product factors and output spatiotemporal drug concentrations in luminal fluid, epithelium, stroma/host cells, and blood. Pharmacodynamic (PD) analysis referenced stroma/host cell concentrations to prophylactic values; summary metrics were time from product insertion to protection (t) and degree of protection (PP). Results incorporated host factors characteristic of population variability. Neural nets (NN) linked simulated blood PK metrics (C, t, AUC, C) to mucosal PK/PD metrics. The NNs delivered high-performance mapping of these multiparametric relationships. Given multi-log variability typical of biopsy data for tenofovir and other topical microbicides, results suggest downstream but higher fidelity measurements in blood could help improve determination of PK and create inferences about PD. Analysis here is for a tenofovir gel, but this approach offers promise for application to other microbicide modalities and to topical drug delivery to vaginal mucosa more generally.
杀微生物剂药代动力学（PK）研究通常在腔液、黏膜组织和血液中采样药物。可以最频繁地在受试者中进行血液测量，连续进行。然而，抗逆转录病毒药物在黏膜组织/细胞中对抗 HIV。我们通过计算模型来预测组织中的浓度，重点是阴道凝胶中递送的抗逆转录病毒药物替诺福韦。确定性 PK 模型输入宿主和产品因素，并输出腔液、上皮、基质/宿主细胞和血液中的时空药物浓度。药效学（PD）分析参考基质/宿主细胞浓度以达到预防值；总结指标是从产品插入到保护的时间（t）和保护程度（PP）。结果纳入了具有人群变异性特征的宿主因素。神经网络（NN）将模拟的血液 PK 指标（C、t、AUC、C）与黏膜 PK/PD 指标联系起来。NN 提供了这些多参数关系的高性能映射。鉴于替诺福韦和其他局部杀微生物剂活检数据的多对数变异性，结果表明血液中的下游但更保真度测量可以帮助确定 PK 并推断 PD。这里的分析适用于替诺福韦凝胶，但这种方法有望应用于其他杀微生物剂模式和更一般地应用于阴道黏膜的局部药物输送。
