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 AUC0-inf compared with single 12- and 24-mg IR doses, respectively. A 
high-fat breakfast increased upadacitinib ER Cmax and AUC0-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 AUC0-24 , comparable Cmax and Cmin 
, 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.