Elucidating Fundamental Principles of Dermal Pharmacokinetics via Microdialysis

项目总结：本项目响应了资助机会RFA-FD-20-019，“生物等效性 局部产品：阐明微透析或微透析皮肤药代动力学的基本原理 微灌注技术（U 01）"。本提案的目的是阐明药代动力学 原理和概念（例如，剂量、药物吸收分数、表观分布容积、Cmax， 在评估局部应用的速率和程度时，应应用或调整AUCinfinity） 化合物在皮肤内的作用部位处或附近的真皮中变得可用。拟议 工作使用体内微透析来表征施用以下药物后的真皮药代动力学 药物（i）通过后透析/微透析方法（真皮输注）直接在真皮中，和（ii）局部， 从皮肤科配方中。这些研究的结果将允许一个彻底的特点 真皮渗透性（吸收），分布，代谢和消除（ADME），这将 阐明生物等效性评估的基本假设是否 全身制剂可以应用于局部制剂。此外，真皮的表征 ADME过程可用于开发新的策略、概念和终点，以解决 局部皮肤病药物产品的生物等效性。

PROJECT SUMMARY: This project responds to Funding Opportunity RFA-FD-20-019, “Bioequivalence of Topical Products: Elucidating Fundamental Principles of Dermal Pharmacokinetics for Microdialysis or Microperfusion Techniques (U01)”. The purpose of this proposal is to elucidate how pharmacokinetic principles and concepts (e.g., dose, fraction of drug absorbed, apparent volume of distribution, Cmax, AUCinfinity) should be applied or adapted when evaluating the rate and extent to which a topically applied compound becomes available in the dermis, at or near a site of action within the skin. The proposed work uses in vivo microdialysis to characterize dermis pharmacokinetics following the administration of drugs (i) directly in dermis via a retrodialysis/microdialysis approach (dermal infusion), and (ii) topically, from dermatological formulations. The results of these studies will permit a thorough characterization of dermis permeability (absorption), distribution, metabolism, and elimination (ADME), which will elucidate whether or not the fundamental assumptions that underlie bioequivalence assessment for systemic formulations can be applied to topical formulations. In addition, characterization of dermal ADME processes can be used to develop new strategies, concepts, and endpoints to address the issue of bioequivalence of topical dermatological drug products.