Pharmacokinetics of Upadacitinib With the Clinical Regimens of the Extended-Release Formulation Utilized in Rheumatoid Arthritis Phase 3 Trials

Upadacitinib is a Janus kinase 1 inhibitor under development for the treatment of several inflammatory disorders including rheumatoid arthritis (RA). Upadacitinib was administered in the phase 2 RA trials primarily as twice-daily regimens of an immediate-release (IR) formulation. The upadacitinib extended-release (ER) formulation was developed to enable once-daily dosing. In the present study, upadacitinib pharmacokinetics were characterized after the administration of single and multiple once-daily doses of the ER formulation in healthy subjects relative to single and multiple twice-daily doses of the IR formulation. Increase in upadacitinib exposure was dose-proportional over the evaluated 15- to 30-mg ER dose range. Single 15- and 30-mg ER doses provided equivalent AUC(0-inf) compared with single 12- and 24-mg IR doses, respectively. A high-fat breakfast increased upadacitinib ER C-max and AUC(0-inf) by only 20% and 17%, respectively, relative to fasting conditions. The median time to peak plasma concentrations was 2 to 4hours for the ER formulation, and steady state was achieved by day 4 of once-daily dosing. Doses of 15 and 30mg once daily using the ER formulation provided equivalent AUC(0-24), comparable C-max and C-min, and a fluctuation index over a 24-hour period at steady state similar to 6 and 12mg twice daily, respectively, using the IR formulation. These results supported the use of upadacitinib 15- and 30-mg doses of the ER formulation in the phase 3 trials in RA.