Progressing integration of in vitro topical formulation characterisation, release and permeation data to the next level - PBPK based extrapolation to bioequivalence assessment in virtual populations

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Project Summary/ Abstract Physiologically Based Pharmacokinetic (PBPK) modelling has become an important part of the drug development process, both for novel and generic drug products. For the later, the USFDA supports the use of modelling and simulation for establishing (virtual) bioequivalence between reference and test products. Incorporation of PBPK modelling can increase confidence in in vitro data and help to reduce or eliminate the need for clinical trials, thus accelerating approval of affordable drug products. The overarching aim of this grant proposal is to progress integration of in vitro data to PBPK models by enhancing the MPML MechDermA model, defining best practices for in vitro data usage, and analysing and re-considering study protocols utilised to generate the data. Aim 1 is to collate and make publically available an extensive database of skin permeability data that can be used to verify and/or optimize PBPK models. This database will also be used in Aim 2 to verify and optimize simulations of different IVPT setups, such as different membrane types, diffusion cell types, etc. The QSARs built in to the MPML MechDermA describing drug partitioning, diffusion and binding will be systematically evaluated, resulting in identification of the best performing combination of QSARs. If necessary new QSARs will be developed to improve ab initio predictions. The verified IVPT module will be enhanced to inform the design of IVPT studies including estimation of receptor solution solubility and LLOQ requirements. Under Aim 3, a comprehensive series of in vitro characterization, release and permeation studies will be conducted, focusing on four formulations of hydrocortisone (HC) and clobetasol propionate (CP). This data will be used in Aim 4 to develop robust PBPK models and subsequently extrapolate to the in vivo scenario, where identified literature data will be leveraged to verify the in vivo models for healthy and diseased populations. Under Aim 5, in-house HC and CP drug products with a modified formulation attribute will be designed and characterized. These modified formulations will be used to challenge the PBPK models, which will verify the Model’s ability to distinguish bio(in)equivalence. As part of this Aim, existing formulation models will be enhanced and models for advanced release technologies such as microspheres and liposomes will be investigated. Aim 6 deals with concurrent excipient/penetration enhancer absorption with a particular focus on propylene glycol. Experimental data on propylene glycol penetration from the clobetasol propionate cream (Aim 2), will be used to study concurrent absorption and account for this using the excipient model in the MPML MechDermA.