Modelling and simulation approaches to support formulation optimization, clinical development and regulatory assessment of the topically applied formulations - Nimesulide solution gel case study.

The objective of the study was to show how mechanistic modelling can be used to characterize the skin absorption of Nimesulide (NIM) in both in vitro systems and in vivo subjects. A basic PBPK model for oral absorption to characterize the systemic disposition of NIM and MPML MechDermATM models for in vitro permeation and in vivo, topical absorption was developed and verified using published data. The developed models utilize drug physicochemical properties, formulation attributes and physiology information either collected from literature and/or from Simcyp databases (systems' data). Following the verification of the PBPK models virtual bioequivalence (VBE) trials were performed both at systemic and local exposure levels (dermis concentrations) to compare these formulations. A parameter sensitivity analysis was conducted to understand the impact of vehicle-related attributes on IVPT (in vitro permeation test) data. The vehicle-stratum corneum lipids partition coefficient in the formulation layer (Kpsc_lip:vehicle) was identified to be an appropriate parameter to take into account the differences in dermal absorption of marketed preparations based on the qualitative composition. Thus, this parameter was optimized for each marketed product based on the published in vitro data. After verification of the IVPT model, IVIVE was performed to assess the predictability of the model for studying the in vivo pharmacokinetics of NIM. The VBE analysis concluded that these formulations are bioequivalent at the level of systemic and local dermis exposure. To summarize, the study shows the use of modelling and simulation (M&S) tools to better understand the behaviour of formulations and their interaction with human physiology.