Development of In Vitro-In Vivo Correlation for Upadacitinib Extended-Release Tablet Formulation

Abstract

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 C_max 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.

Keywords: ABT-494; extended-release formulation; in vitro/in vivo correlations (IVIVC); pharmacokinetics; upadacitinib.

Fig. 1

Cumulative percent dissolved (mean ± SD) versus time profiles for upadacitinib ER formulations containing 10% HPMC (formulation A), 15% HPMC (formulation B), 20% HPMC (formulation C; target formulation), and 35% HPMC (formulation D). F2 values comparing the four formulations are presented

Fig. 2

Mean upadacitinib plasma concentration versus time profiles following administration of IR capsule and ER tablet formulations of upadacitinib. ER formulations of upadacitinib contained 10% HPMC (formulation A), 15% HPMC (formulation B), 20% HPMC (formulation C; target formulation), and 35% HPMC (formulation D). Insert: Log-linear scale of mean upadacitinib plasma concentration versus time profiles following administration of IR capsule and ER tablet formulations of upadacitinib

Fig. 3

Point Estimates and 90% confidence intervals for the bioavailability of upadacitinib following administration of single doses of upadacitinib 30 mg extended-release tablets with different release rates relative to single 24 mg dose of the upadacitinib immediate-release capsules

Fig. 4

Mean in vivo absorption versus time profile of upadacitinib extended-release formulations based on numerical deconvolution

Fig. 5

Correlation between a the observed fraction absorbed and the fraction dissolved and b in vivo absorption time and in vitro dissolution time for upadacitinib ER formulations