Simulations Plus, Incorporated, 42505 10th Street West, Lancaster, California, 93534, USA.
Office of Research and Standards (ORS), Office of Generic Drugs (OGD), Center for Drug Evaluation and Research (CDER), U.S. Food and Drug Administration (FDA), Silver Spring, Maryland, USA.
AAPS PharmSciTech. 2024 Feb 17;25(3):39. doi: 10.1208/s12249-024-02740-x.
Quantitative in silico tools may be leveraged to mechanistically predict the dermato-pharmacokinetics of compounds delivered from topical and transdermal formulations by integrating systems of rate equations that describe permeation through the formulation and layers of skin and pilo-sebaceous unit, and exchange with systemic circulation via local blood flow. Delivery of clobetasol-17 propionate (CP) from Dermovate cream was simulated using the Transdermal Compartmental Absorption & Transit (TCAT) Model in GastroPlus. The cream was treated as an oil-in-water emulsion, with model input parameters estimated from publicly available information and quantitative structure-permeation relationships. From the ranges of values available for model input parameters, a set of parameters was selected by comparing model outputs to CP dermis concentration-time profiles measured by dermal open-flow microperfusion (Bodenlenz et al. Pharm Res. 33(9):2229-38, 2016). Predictions of unbound dermis CP concentrations were reasonably accurate with respect to time and skin depth. Parameter sensitivity analyses revealed considerable dependence of dermis CP concentration profiles on drug solubility in the emulsion, relatively less dependence on dispersed phase volume fraction and CP effective diffusivity in the continuous phase of the emulsion, and negligible dependence on dispersed phase droplet size. Effects of evaporative water loss from the cream and corticosteroid-induced vasoconstriction were also assessed. This work illustrates the applicability of computational modeling to predict sensitivity of dermato-pharmacokinetics to changes in thermodynamic and transport properties of a compound in a topical formulation, particularly in relation to rate-limiting steps in skin permeation. Where these properties can be related to formulation composition and processing, such a computational approach may support the design of topically applied formulations.
定量计算工具可以通过整合描述化合物经局部和透皮制剂透过皮肤和毛囊皮脂腺单位以及与局部血流交换进入全身循环的速率方程系统，从机制上预测化合物的经皮药代动力学。利用 GastroPlus 中的经皮隔室吸收与传递（TCAT）模型对 Dermovate 乳膏中的氯倍他索-17-丙酸酯（CP）进行了递送模拟。将乳膏视为水包油乳剂，使用公开可得的信息和定量构效关系估算模型输入参数。根据模型输入参数的可用值范围，通过将模型输出与通过皮肤开放式微灌注（Bodenlenz 等人，Pharm Res. 33(9):2229-38, 2016）测量的 CP 真皮浓度-时间曲线进行比较，选择了一组参数。未结合 CP 真皮浓度的预测结果与时间和皮肤深度具有较好的相关性。参数敏感性分析表明，真皮 CP 浓度曲线对药物在乳剂中的溶解度、乳剂中分散相体积分数和 CP 在连续相中的有效扩散系数具有较大的依赖性，对分散相液滴尺寸的依赖性可忽略不计。还评估了乳膏中水分蒸发损失和皮质激素引起的血管收缩对 CP 经皮药代动力学的影响。该工作说明了计算建模在预测局部制剂中化合物经皮药代动力学对热力学和传输性质变化的敏感性方面的适用性，特别是在与皮肤渗透的限速步骤相关时。在这些性质可以与制剂组成和加工相关的情况下，这种计算方法可能支持局部应用制剂的设计。
