In Vitro-In Vivo Correlation (IVIVC) in Transdermal Drug Delivery Systems: Models, Regulatory Perspectives and Translational Challenges.

Transdermal drug delivery systems (TDDS) represent a clinically established yet mechanistically complex platform for systemic drug administration, offering advantages such as avoidance of hepatic first-pass metabolism, sustained drug input and improved patient adherence. However, their development and regulatory evaluation remain challenging due to the physiological variability of the skin barrier, site-dependent absorption and formulation-skin interactions. In vitro-in vivo correlation (IVIVC) has therefore emerged as a critical translational framework for linking in vitro permeation characteristics with systemic pharmacokinetic outcomes and thereby supporting formulation optimization, regulatory decision-making and reduction of repetitive clinical studies. This review provides a comprehensive and integrative analysis of IVIVC in TDDS, encompassing experimental methodologies, mechanistic modelling strategies, regulatory perspectives and translational challenges. Emphasis is placed on the limitations of classical empirical correlations when applied to transdermal systems, where lag time, cutaneous depot formation and nonlinear absorption frequently violate traditional IVIVC assumptions. Mechanistic and physiologically based pharmacokinetic (PBPK) approaches are highlighted as more robust alternatives capable of incorporating skin physiology, variability and formulation-specific effects. Evidence from successful and unsuccessful case studies demonstrates that predictive IVIVC is achievable but strongly dependent on methodological standardisation, model validity and physiological representation. Regulatory frameworks currently regard IVIVC primarily as a supportive tool; however, increasing integration with Quality-by-Design (QbD) principles, model-informed drug development (MIDD) and advanced experimental platforms indicates growing acceptance. The review ultimately reframes IVIVC for TDDS as a continuum of translational strategies rather than a binary outcome and identifies key knowledge gaps whose resolution will be essential for advancing predictive, regulatorily trusted IVIVC models for next-generation transdermal therapeutics.