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

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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