Assessment of effect of CYP3A inhibition, CYP induction, OATP1B inhibition, and high-fat meal on pharmacokinetics of the JAK1 inhibitor upadacitinib

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 3mg 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 400mg once-daily ketoconazole. In Study 2, a 12mg upadacitinib dose was administered alone, with the first, and with the eighth dose of a 9-day regimen of rifampin 600mg once daily. Upadacitinib plasma concentrations were characterized. RESULTS Administration of upadacitinib immediate-release capsules after a high-fat meal decreased upadacitinib C-max by 23% and had no impact on upadacitinib AUC relative to the fasting conditions. Ketoconazole (strong CYP3A inhibitor) increased upadacitinib C-max and AUC by 70% and 75%, respectively. Multiple doses of rifampin (broad CYP inducer) decreased upadacitinib C-max 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.