The Impact of Using Measured In Vitro Data to Develop Physiologically Based Pharmacokinetic Models of Dermal...

In vitro permeation testing (IVPT) is commonly used to assess dermal drug delivery, yet its utility can be challenged by high variability and the need for large sample sizes to achieve sufficient statistical power. Dermal physiologically based pharmacokinetic (PBPK) models provide a mechanistic approach to better interpret IVPT results and to extrapolate in vitro to in vivo. In the present work, a dermal PBPK model for caffeine was developed using a bottom-up approach with minimal parameter optimization. The model incorporated formulation characteristics, experimentally measured skin partition coefficients, and predicted diffusion coefficients, while explicitly accounting for the constraints associated with the analytical methods used in each IVPT, improving the model's predictive reliability compared to previous work. After validation against literature IVPT data for aqueous solutions, the model was extended to simulate permeation from ointments and emulsions. The model was used to extrapolate and predict in vivo skin concentrations following application of gel formulations containing a chemical penetration enhancer, propylene glycol. For the emulsion formulations, the model was utilised to explore virtual bioequivalence and define a preliminary "safe space" for bioequivalence, offering insights to support both drug product development and regulatory submissions.