Assessment of effect of CYP3A Inhibition, CYP Induction, OATP1B Inhibition, and High-Fat Meal on Pharmacokinetics of the JAK1 inhibitor Upadacitinib

Summary

Aims

Upadacitinib (ABT-494) is a selective Janus kinase 1 inhibitor 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, 2-sequence cross-over 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 1^st, and with the 8^th doses 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 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 coadministered with ketoconazole, rifampin, or after a high-fat meal.

Conclusions

Strong CYP3A inhibition and broad CYP induction results in a weak and a moderate effect, respectively, on upadacitinib exposures. OATP1B inhibition and administration of upadacitinib immediate-release formulation with food does not impact upadacitinib exposure.

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