Mechanistic dermal patch modelling for fentanyl: Linking in vitro release and permeation data to a physiologically based pharmacokinetic approach

Abstract

Dermal physiologically based pharmacokinetic (PBPK) models can be informed by various types of data. In vitro permeation testing (IVPT) experiments aid parameterisation of skin permeation independent of the complexities of systemic uptake. In vitro release testing (IVRT) studies isolate the formulation parameters by utilising a synthetic membrane. Leveraging this data in dermal PBPK model development, via an IVRT - IVPT - in vivo (IVIVIV) workflow, can reduce identifiability issues arising from concurrent parameterisation of formulation and skin permeation, or fitting directly to clinical data. In this work, three fentanyl matrix patch formulations were modelled with this approach using the Simcyp MPML MechDermA simulator. Mechanistic patch models were developed for each of the three different formulations, using IVRT data to parameterise formulation differences. These formulation models were coupled to a fentanyl skin absorption model in Simcyp’s IVPT Module to simulate IVPT data. The resulting model each formulation was used to extrapolate and predict in vivo application, with validation against clinical data. A virtual bioequivalence study was conducted to investigate bioequivalence given differing geometries and characteristics. A validated fentanyl patch model was used to predicted plasma profiles for patches that suffered manufacturing defects, as a risk assessment exemplifying PBPK model utilisation.