Optimized clinical dermal Open Flow Microperfusion study design to demonstrate bioequivalence based on cutaneous pharmacokinetics

优化临床皮肤开放式微灌注研究设计，以证明基于皮肤药代动力学的生物等效性

• 批准号: 10598961
• 负责人: Frank Sinner
• 金额: $ 25万
• 依托单位: JOANNEUM RESEARCH FORSCHUNGSGESELLSCHAFT MBH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10598961
• 关键词: Optimized; clinical; dermal; Open; Flow

PROJECT SUMMARY/ABSTRACT Topically Applied Drug Products (TADPs) have experienced an extraordinary price increase in the USA, mostly due to a lack of generic TADPs. Development of generic TAPDs is hindered by high costs and risk associated with clinical endpoint studies required to show bioequivalence (BE) of prospective generic TADPs to their reference products. The barrier to develop a generic TADP has been reduced by the introduction of a characterization-based BE approach by US-FDA. Following this in-vitro approach, generic products whose components (Q1), composition (Q2), and arrangement of matter (Q3) are precisely matched to those of the reference product are developed, and BE may be shown by combinations of In Vitro Release Testing, In Vitro Permeation Testing and Q3 characterization. Unfortunately, a significant part of TADPs do not qualify for this in-vitro option as they cannot match sameness with regard to the component concentrations within the required +/- 5% window. There is an urgent need for alternatives to show BE for TADPs in which there is uncertainty in the matching of Q2 and Q3 between the generic and reference product, and for non-Q1/non-Q2/Q3 generic TADPs, especially for Q1 and Q2 similar products. The multidisciplinary project beOFM will continue the work of two successfully finished US-FDA co-funded projects, in which dermal Open Flow Microperfusion (dOFM) has shown its potential to accurately and sensitively assess the rate and extent of drugs at or near their site of action, and in which dOFM was able to show cutaneous BE for several TADPs to themselves and to US-FDA approved generic TADPs bearing APIs such as acyclovir, lidocaine, prilocaine, and diclofenac. beOFM will elucidate the impact of drug residence time on drug PK in the stratum corneum, epidermis, and dermis, and the relationship between the free drug versus protein-bound drug sampled with different continuous sampling techniques (dOFM, dermal microdialysis (dMD), epidermal microfluidics (eMF)) as well as tape stripping and depth-resolved skin biopsies in parallel. Further, beOFM will develop and implement PK models optimized for dOFM/dMD that are able to predict dOFM/dMD PK profiles, including appropriate PK endpoints for establishing BE using cutaneous PK-based approaches for topical drugs that may not reach the maximum drug concentration within 24 hours post-administration. All project results will be combined in the overall goal to develop a universal, standardized approach for cost- and time-optimized clinical cutaneous BE study designs using dOFM and dMD. The applicability of this new approach will be verified by performing a cutaneous BE dOFM study of a TADP that has not been investigated clinically by dOFM so far. beOFM will build the scientific basis for cutaneous BE studies using dermal continuous sampling techniques for Q1 and Q2 similar products that do not qualify for the in-vitro approach, thus reducing existing barriers in generic TADP development/approval and help to increase the availability of high-quality and affordable generic TADPs. 1

项目总结/摘要 局部应用药物产品（TADPs）在美国经历了异常的价格上涨， 主要是因为缺乏通用的TADP。仿制TAPD的开发受到高成本和高风险的阻碍 与证明前瞻性仿制药生物等效性（BE）所需的临床终点研究相关 TADP与其参比产品。开发仿制药TADP的障碍已经减少， US-FDA引入基于特征的BE方法。按照这种体外方法， 其成分（Q1）、组成（Q2）和物质排列（Q3）精确地 与参比产品相匹配，BE可由In 体外释放测试、体外渗透测试和Q3表征。不幸的是， 部分TADPs不符合此体外选项的条件，因为它们无法与 组分浓度在要求的+/- 5%窗口内。迫切需要替代品 为了显示TADP的BE，其中在通用和通用之间的Q2和Q3匹配中存在不确定性， 参考产品，以及非Q1/非Q2/Q3通用TADP，尤其是Q1和Q2类似产品。 多学科项目beOFM将继续两个成功完成的美国FDA共同资助的工作 在这些项目中，真皮开放流微灌注（dOFM）已显示出其准确和 敏感地评估药物在其作用部位或附近的速率和程度，以及dOFM能够 显示几种TADP的皮肤BE，以及US-FDA批准的通用TADP， 原料药，如阿昔洛韦、利多卡因、丙胺卡因和双氯芬酸。 beOFM将阐明药物停留时间对角质层、表皮 和真皮，以及游离药物与蛋白结合药物之间的关系， 连续采样技术（dOFM、皮肤微透析（dMD）、表皮微流体（eMF））， 以及并行进行胶带剥离和深度分辨皮肤活组织检查。此外，beOFM将开发和 实施针对dOFM/dMD优化的PK模型，能够预测dOFM/dMD PK特征，包括 使用基于皮肤PK的局部药物方法确定BE的适当PK终点， 给药后24小时内可能达不到最大药物浓度。 所有项目成果都将纳入总体目标，以制定一个通用的标准化方法， 使用dOFM和dMD进行成本和时间优化的临床皮肤BE研究设计。的适用性 这一新方法将通过对尚未被治疗的TADP进行皮肤BE dOFM研究来验证。 到目前为止，dOFM进行了临床研究。beOFM将使用以下方法为皮肤BE研究建立科学基础 不符合体外试验条件的Q1和Q2类似产品的皮肤连续采样技术 方法，从而减少了通用TADP开发/批准的现有障碍，并有助于增加 提供高质量和负担得起的仿制药TADP。 1