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

项目摘要/摘要 局部应用药品(TADP)在美国经历了异常的价格上涨， 主要是由于缺乏通用的TADP。高成本和高风险阻碍了非专利药品的开发 与临床终点研究相关，需要证明未来仿制药的生物等效性(BE) TADP到他们的参考产品。开发通用TADP的障碍已经通过 美国食品和药物管理局介绍了一种基于特征的BE方法。遵循这一体外方法，通用 其成分(Q1)、组成(Q2)和物质排列(Q3)精确为 与参考产品的那些匹配，并且BE可以通过In的组合来表示 体外释放试验、体外渗透试验和Q3表征。不幸的是，一个重要的 部分TADP不符合这一体外选择的条件，因为它们不能匹配关于 所需的+/-5%窗口内的组分浓度。迫切需要有替代方案 为了显示对于TADP的BE，在TADP中，在通用和 参考产品，以及非第一季度/第二季度/第三季度通用TADP，特别是第一季度和第二季度类似产品。 多学科项目BeOFM将继续两个成功完成的美国-FDA共同资助的项目的工作 在这些项目中，真皮开放流量微灌流(DOFM)已经显示出其准确和 敏感地评估药物在其作用部位或附近的速度和程度，以及DOFM在哪些部位能够 向他们自己和美国FDA批准的通用TADP显示皮肤是几个TADP的轴承 阿昔洛韦、利多卡因、普利洛卡因和双氯芬酸等原料药。 BeOFM将阐明药物停留时间对药物在角质层，表皮， 和真皮，以及不同样品中游离药物与蛋白质结合药物之间的关系 连续采样技术(DOFM、真皮微渗析(DMD)、表皮微流体(EMF)) 以及并行的胶带剥离和深度分辨皮肤活检。此外，BeOFM将发展和 实施针对DOFM/DMD进行优化的能够预测DOFM/DMD PK配置文件的PK模型，包括 使用基于皮肤PK的方法建立BE的适当PK终点 在服药后24小时内可能达不到最大药物浓度。 所有项目成果将合并到总目标中，以制定一种通用、标准化的方法 使用DOFM和DMD的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接受治疗的TADP进行皮试研究来验证。 到目前为止，DOFM已经进行了临床调查。BeOFM将为皮肤BE研究奠定科学基础 不符合体外试验条件的Q1和Q2类似产品的真皮连续取样技术 方法，从而减少通用TADP开发/审批中的现有障碍，并有助于增加 提供高质量和负担得起的非专利TADP。 1

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