Elucidating Fundamental Principles of Dermal Pharmacokinetics via Microdialysis

项目摘要：本项目响应资助机会RFA-FD-20-019，“生物等效性 外用产品：阐明微透析或药物治疗皮肤药代动力学的基本原理 微灌注技术(U01)“。这项建议的目的是阐明药代动力学 原理和概念(例如，剂量、药物吸收比例、表观分布体积、Cmax、 AUCinfinity)在评估局部应用的速度和程度时应加以应用或调整 化合物在真皮中、在皮肤内的作用部位或附近可用。建议数 Work使用体内微透析来表征给药后的真皮药代动力学 药物(I)通过反透析/微透析方法(皮肤输注)直接进入真皮，以及(Ii)局部， 来自皮肤科的配方。这些研究的结果将使我们能够彻底地描述 真皮渗透性(吸收)、分布、代谢和消除(ADME)，这将 阐明作为生物等效性评价基础的基本假设是否 系统性制剂可应用于外用制剂。此外，真皮的特征 ADME流程可用于开发新的战略、概念和端点，以解决 皮肤科外用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.