Skin physiologically based pharmacokinetic modeling: current research progress, software comparison, and future...

Transdermal and topical delivery systems (TDS) have emerged as the third-largest route of administration due to their ability to bypass first-pass metabolism and maintain stable plasma concentrations. Skin physiologically based pharmacokinetic (PBPK) models mechanistically characterize the percutaneous absorption process, predict local and systemic exposure, and enhance research and development efficiency through virtual clinical trials. This paper first elaborates on the theoretical foundation of skin PBPK modeling based on Fick's second law of diffusion and compares the model assumptions and application scenarios of four well-established and validated modeling platforms: Simcyp, GastroPlus, Skin-CAD, and PK-Sim. The findings indicate that Simcyp provides a refined depiction of skin physiological structure and is widely applied in clinical evaluation and special population prediction. GastroPlus focuses more on the mechanistic description of TDS formulations. Skin-CAD, as a specialized software, is extensively utilized for in vitro-in vivo extrapolation (IVIVE) predictions and formulation optimization. PK-Sim, as a freely accessible open-source software, has been used to investigate the physiological ontogeny of skin in pediatric populations. However, existing studies share limitations such as highly inconsistent model structures with varying complexity, challenges in acquiring accurate parameters, and a scarcity of physiological information for special populations. Future research should prioritize optimizing parameter acquisition methods and broadening physiological databases for pediatric, geriatric, and skin-lesion populations. Additionally, integrating non-invasive imaging technologies to construct high-precision 'digital twin' skin models represents a critical future direction. These advancements will drive the transition of PBPK models from descriptive tools to supportive instruments for individualized dosing and regulatory decision-making.