AIMS: Upadacitinib (ABT-494) is a selective Janus kinase 1 inhibitor being 
developed for treatment of auto-immune inflammatory disorders. This work 
evaluated effects of high-fat meal, cytochrome P450 (CYP) 3A inhibition, CYP 
induction, and organic anion transporting polypeptide (OATP) 1B inhibition on 
upadacitinib pharmacokinetics.
METHODS: Two Phase 1 evaluations were conducted, each in 12 healthy subjects. In 
Study 1, using a randomized, two-sequence crossover design, a 3 mg dose of 
upadacitinib (immediate-release capsules) was administered alone under fasting 
conditions, after high-fat meal, or on Day 4 of a 6-day regimen of 400 mg 
once-daily ketoconazole. In Study 2, a 12 mg upadacitinib dose was administered 
alone, with the first, and with the eighth dose of a 9-day regimen of rifampin 
600 mg once daily. Upadacitinib plasma concentrations were characterized.
RESULTS: Administration of upadacitinib immediate-release capsules after a 
high-fat meal decreased upadacitinib Cmax by 23% and had no impact on 
upadacitinib AUC relative to the fasting conditions. Ketoconazole (strong CYP3A 
inhibitor) increased upadacitinib Cmax and AUC by 70% and 75%, respectively. 
Multiple doses of rifampin (broad CYP inducer) decreased upadacitinib Cmax and 
AUC by approximately 50% and 60%, respectively. A single dose of rifampin (also 
an OATP1B inhibitor) had no effect on upadacitinib AUC. Upadacitinib was well 
tolerated when co-administered with ketoconazole, rifampin, or after a high-fat 
meal.
CONCLUSIONS: Strong CYP3A inhibition and broad CYP induction result in a weak 
and moderate effect, respectively, on upadacitinib exposures. OATP1B inhibition 
and administration of upadacitinib immediate-release formulation with food does 
not impact upadacitinib exposure.