An integrated biophysical model for predicting the clinical pharmacokinetics of transdermally delivered compounds

The delivery of therapeutic drugs through the skin is a promising alternative to oral or parenteral delivery routes because dermal drug delivery systems (D³Ss) offer unique advantages, such as controlled drug release over sustained periods and a significant reduction in first-pass effects, thus reducing the required dosing frequency and the level of patient noncompliance. Furthermore, D³Ss find applications in multiple therapeutic areas, including drug repurposing. This article presents an integrated biophysical model of dermal absorption for simulating the permeation and absorption of compounds delivered transdermally. The biophysical model is physiologically/biologically inspired and combines a holistic model of healthy skin with whole-body physiology-based pharmacokinetics through the dermis microcirculation. The model also includes the effects of chemical penetration enhancers and hair follicles on transdermal transport. The model-predicted permeation and pharmacokinetics of select compounds were validated using in vivo data reported in the literature. We conjecture that the integrated model can be used to gather insights into the permeation and systemic absorption of transdermal formulations (including cosmetic products) released from novel depots and to optimize delivery systems. Furthermore, the model can be extended to diseased skin with parametrization and structural adjustments specific to skin diseases.