Mechanistic Modelling of Lidocaine and Prilocaine Absorption from EMLA Cream upon Topical Application using Physiologically Based Pharmacokinetic Modelling.

Physiologically based pharmacokinetic (PBPK) modelling can be utilized in dermal drug development and to support regulatory assessments by integrating information related to the active pharmaceutical ingredient (API), drug product, and skin physiology into a mechanistic simulation framework. The purpose of this study was to develop a mechanistic skin absorption model to predict the absorption of lidocaine and prilocaine following topical application of EMLA cream (lidocaine/prilocaine topical cream, 2.5%/2.5%) in virtual subjects. The multi-phase multi-layer mechanistic dermal absorption (MPML MechDermA™) model was used to simulate in vitro permeation of both APIs. Changes in formulation pH post application were studied experimentally, and these dynamic changes were captured in the model when simulating finite dose studies using ex vivo human skin. A dermal in vivo PBPK model for the EMLA cream (lidocaine/prilocaine topical cream, 2.5%/2.5%) was developed and validated. The model was able to consider the formulation and trial design differences of in vivo studies and adequately simulated the observed data. Further model validation was performed against a manufactured cream with microstructural characteristics that were different compared to the EMLA cream. Through virtual bioequivalence assessments, the in vivo model demonstrated that it may be used to predict the impact of differences in drug product quality attributes on the in vivo performance of a topically applied drug product and inform decisions related to product development.