The aim of this study was to characterize the effects of upadacitinib, a Janus 
kinase 1 inhibitor, on in vivo activity of different cytochrome P450 (CYP) 
enzymes using a cocktail approach. Healthy subjects (n = 20) received single 
oral doses of the modified Cooperstown 5+1 cocktail drugs (midazolam [CYP3A], 
caffeine [CYP1A2], warfarin + vitamin K [CYP2C9], omeprazole [CYP2C19], and 
dextromethorphan [CYP2D6]) without upadacitinib and on day 11 (midazolam) or 12 
(all other probes) of a 15-day regimen of upadacitinib 30 mg once daily 
(extended-release formulation). Serial blood samples and 12-hour urine samples 
were collected for assays of the probe substrates and select metabolites. The 
ratio (90%CI) of area under the plasma concentration-time curve from time 0 to 
infinity (AUCinf ) central values when the cocktail drugs were administered with 
upadacitinib relative to when administered alone were 0.74 (0.68-0.80) for 
midazolam, 1.22 (1.15-1.29) for caffeine, 1.11 (1.07-1.15) for S-warfarin, 1.07 
(0.95-1.22) for dextromethorphan, and 0.82 (0.72-0.94) for omeprazole. The ratio 
(90%CI) was 1.09 (1.00-1.19) for 5-hydroxy-omeprazole to omeprazole AUCinf ratio 
and 1.17 (0.97-1.41) for dextromethorphan to dextrorphan 12-hour molar urinary 
ratio. Upadacitinib 30 mg once daily (a dose that is twice the optimal dose in 
rheumatoid arthritis based on phase 3 results) has a limited effect on CYP3A 
activity (26% decrease in exposure of midazolam, a sensitive CYP3A substrate) 
and no relevant effects on CYP1A2, CYP2C9, CYP2C19, or CYP2D6 activity in vivo. 
No clinically relevant changes in plasma exposures are expected for drugs that 
are substrates for the evaluated CYP enzymes when coadministered with 
upadacitinib.