Exploration of IVIVC Deconvolution Methods in a PBPK Platform: Case Example with Tofacitinib

Modified-release (MR) drug products are designed to provide controlled drug delivery over time, offering therapeutic and compliance advantages. However, ensuring consistent in vivo performance requires a thorough understanding of the relation between in vitro dissolution behavior and in vivo drug absorption. In vitro-in vivo correlation (IVIVC) serves as a critical tool in this context, enabling formulation optimization, supporting regulatory decision-making, and streamlining product development. This study aimed to use tofacitinib as a model compound to evaluate three deconvolution methodologies within GPX™ - numerical, compartmental, and mechanistic. Prototype formulations with varying release rates were assessed in a randomized crossover study in healthy volunteers. In vivo fraction absorbed profiles were derived and convoluted to simulate plasma concentration-time profiles, which were then compared to observed clinical data. Prediction errors for key pharmacokinetic parameters (i.e., plasma C_max and AUC) were determined, and 90% confidence intervals for both parameters were calculated to assess bioequivalence between the simulated (convoluted) and observed plasma profiles. The results demonstrate the utility of deconvolution-based IVIVC models for MR product development in a physiologically-based pharmacokinetic (PBPK) framework and offer a strategy for assessing dissolution variability in support of regulatory flexibility and robust formulation lifecycle management.