Department of Biomedical Engineering, Duke University, Durham, North Carolina, United States of America.
PLoS One. 2013 Sep 11;8(9):e74404. doi: 10.1371/journal.pone.0074404. eCollection 2013.
Trials of a vaginal Tenofovir gel for pre-exposure prophylaxis (PrEP) for HIV have given conflicting results. Knowledge of concentrations of Tenofovir and its active form Tenofovir diphosphate, at putative sites of anti-HIV functioning, is central to understanding trial outcomes and design of products and dosage regimens. Topical Tenofovir delivery to the vaginal environment is complex, multivariate and non-linear; determinants relate to drug, vehicle, dosage regimen, and environment. Experimental PK methods cannot yield mechanistic understanding of this process, and have uncontrolled variability in drug sampling. Mechanistic modeling of the process could help delineate its determinants, and be a tool in design and interpretation of products and trials.
We created a four-compartment mass transport model for Tenofovir delivery by a gel: gel, epithelium, stroma, blood. Transport was diffusion-driven in vaginal compartments; blood concentration was time-varying but homogeneous. Parameters for the model derived from in vitro and in vivo PK data, to which model predictions gave good agreement. Steep concentration gradients occurred in stroma ≤ 8 hours after gel release. Increasing epithelial thickness delayed initial TFV delivery to stroma and its decline: tmax increased but AUC at 24 hours was not significantly altered. At 24 and 48 hours, stromal concentrations were 6.3% and 0.2% of C(max). Concentrations in simulated biopsies overestimated stromal concentrations, as much as ∼5X, depending upon time of sampling, biopsy thickness and epithelial thickness.
There was reasonably good agreement of model predictions with clinical PK data. Conversion of TFV to TFV-DP was not included, but PK data suggest a linear relationship between them. Thus contrasts predicted by this model can inform design of gels and dosage regimens in clinical trials, and interpretation of PK data. This mass transport based approach can be extended to TFV conversion to TFV-DP, and to other drugs and dosage forms.
临床试验表明，阴道用替诺福韦凝胶用于 HIV 暴露前预防（PrEP）的效果喜忧参半。了解替诺福韦及其活性形式替诺福韦二磷酸在假定的抗 HIV 作用部位的浓度，对于理解试验结果以及产品和剂量方案的设计至关重要。替诺福韦向阴道环境的局部递送过程复杂、多变量且非线性；决定因素与药物、载体、剂量方案和环境有关。实验性 PK 方法无法对该过程提供机制上的理解，且在药物取样方面具有不可控的变异性。该过程的机制建模有助于阐明其决定因素，并成为产品和试验设计和解释的工具。
我们创建了一个替诺福韦凝胶阴道给药的四房室质量传递模型：凝胶、上皮、基质、血液。阴道隔室中的药物转运是扩散驱动的；血液浓度随时间变化但均匀。模型参数源自体外和体内 PK 数据，模型预测与这些数据吻合良好。凝胶释放后 8 小时内基质中出现陡峭的浓度梯度。上皮厚度增加会延迟替诺福韦最初向基质的传递及其衰减：tmax 增加，但 24 小时时 AUC 没有显著改变。在 24 小时和 48 小时时，基质中的浓度分别为 Cmax 的 6.3%和 0.2%。模拟活检中的浓度比基质浓度高估，取决于采样时间、活检厚度和上皮厚度，最大可达 5 倍。
模型预测与临床 PK 数据具有较好的一致性。未包括替诺福韦向替诺福韦二磷酸的转化，但 PK 数据表明它们之间存在线性关系。因此，该模型预测的差异可以为临床试验中凝胶和剂量方案的设计以及 PK 数据的解释提供信息。这种基于质量传递的方法可以扩展到替诺福韦向替诺福韦二磷酸的转化，以及其他药物和剂型。
