Development of a mechanistic in vitro-in vivo correlation for upadacitinib using physiologically-based...

A physiologically-based pharmacokinetic (PBPK) model was successfully developed to describe the absorption, distribution, metabolism, and excretion processes for the upadacitinib 15 mg, 30 mg, and 45 mg extended-release (ER) formulations. A prior numerical in vitro-in vivo correlation (IVIVC) was established for the 15 mg and 30 mg ER formulations. A novel dissolution method had to be developed to achieve adequate in vitro upadacitinib release from the 45 mg ER formulation. A PBPK model was developed and an IVIVC using the 15 mg, 30 mg, and 45 mg ER formulations was incorporated to establish a mechanistic IVIVC framework. Importantly, the more comprehensive mechanistic IVIVC model demonstrated robustness through both internal and external validation and was able to accurately predict in vivo upadacitinib exposures in a distinct clinical trial data set using the 45 mg ER tablet in vitro dissolution data. Further, the model was able to discriminate between 15 mg, 30 mg, and 45 mg exposures. As outlined and encouraged by regulatory guidances, this validated Level A mechanistic IVIVC can serve as a surrogate for bioavailability testing, be a screening tool for future upadacitinib formulation dissolution, and set clinically relevant dissolution acceptance criteria.