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 4 hours for the ER formulation, and steady state was achieved by day 4 of once‐daily dosing. Doses of 15 and 30 mg 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 12 mg 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.