Upadacitinib is a selective Janus Kinase 1 inhibitor which is being developed 
for the treatment of several inflammatory diseases including rheumatoid 
arthritis. Upadacitinib was evaluated in Phase 3 studies as an oral 
extended-release (ER) formulation administered once daily. The purpose of this 
study was to develop a level A in vitro-in vivo correlation (IVIVC) for 
upadacitinib ER formulation. The pharmacokinetics of four upadacitinib 
extended-release formulations with different in vitro release characteristics 
and an immediate-release capsule formulation of upadacitinib were evaluated in 
20 healthy subjects in a single-dose, randomized, crossover study. In vivo 
pharmacokinetic data and in vitro dissolution data (USP Dissolution Apparatus 1; 
pH 6.8; 100 rpm) were used to establish a level A IVIVC. Three formulations were 
used to establish the IVIVC, and the fourth formulation was used for external 
validation. A non-linear IVIVC best described the relationship between 
upadacitinib in vitro dissolution and in vivo absorption profiles. The absolute 
percent prediction errors (%PE) for upadacitinib Cmax and AUC were less than 10% 
for all three formulations used to establish the IVIVC, as well as for the %PE 
for the external validation formulation and the overall mean internal 
validation. Model was cross-validated using the leave-one-out approach; all 
evaluated cross-validation runs met the regulatory acceptance criteria. A level 
A IVIVC was successfully developed and validated for upadacitinib ER 
formulation, which meets the FDA and EMA regulatory validation criteria and can 
be used as surrogate for in vivo bioequivalence.