Physiologically Based Biopharmaceutics and Pharmacokinetics of Drug Products for Dermal Absorption in Humans

摘要 在这里，我们寻求帮助FDA评估局部产品，通过开发， 评估和改进基于生理的吸收和治疗框架 响应FDA号召的皮肤吸收药代动力学模型：生理学 基于非胃肠吸收和药代动力学的建模与仿真 人体吸收药物产品(RFA-FD-14-012)，侧重于皮肤吸收。 我们描述了三个基于生理的药代动力学模型的框架，以帮助 此评估： 1.基于拉普拉斯变换解的解析解 2.区分的方法 3.三维数值分析，以精确模拟角质层和 当产品涂在皮肤上时发生的过程，如某些物质的蒸发 辅料，活性辅料和一些辅料对皮肤的渗透并转移到 深层组织和体循环 然后通过参数敏感度分析验证了这一工作，并与 通过实际数据观察和一些内部验证研究进行预测。 最后阶段是使用来自2个CRO和2个FDA研究的数据对模型进行评估 目前正在支持涉及体外膜，体外皮肤渗透，体外 角质层试验、活体角质层试验和真皮试验。一把钥匙 这里的结果，以及对数据的充分描述，是对 研究对象内部和对象间的可变性以及可能的协方差。 我们的主要目标是预测其作用部位和血液中的活性浓度。 时间到了。

Abstract Here we seek to assist the FDA in its evaluation of topical products by developing, evaluating and improving a framework of physiologically based absorption and pharmacokinetic models for dermal absorption in response to the FDA call: Physiologically Based Absorption and Pharmacokinetic Modeling and Simulation for Non-gastrointestinally Absorbed Drug Products in Humans (RFA-FD-14-012), focusing on dermal absorption. We describe a framework of three physiologically based pharmacokinetic models to assist in this evaluation: 1. An analytical solution based on a Laplace Transform solution 2. A compartmental approach 3. A 3D numerical analysis to precisely mimic the geometry of the stratum corneum and processes that occur when a product is applied to the skin eg evaporation of some excipients, penetration of active and some excipients into the skin and transfer to deeper tissue and the systemic circulation This work is then validated by parameter sensitivity analyses, a comparison with of predictions with actual data observations and some in house validation studies. The final stage is an evaluation of the models using data from 2 CROs and 2 studies FDA are presently supporting that involve in vitro membrane, in vitro skin penetration, in vitro stratum corneum assays, in vivo stratum corneum assays and dermal assays. A key outcome here, as well as an adequate description of the data, is a population description of intra and intersubject variability and likely covariances. Our key goal is to predict active concentrations at their sites of action and in the blood over time.