Background/Purpose:

ABT‑494 is an oral selective JAK1 inhibitor that is being developed for treatment of rheumatoid arthritis and Crohn’s disease.  ABT-494 is metabolized by cytochrome P450 (CYP) enzymes including CYP3A and approximately 20% of the dose is eliminated unchanged in urine. The objectives of this work were to assess the effect of high-fat meal, ketoconazole (a strong CYP3A inhibitor), and rifampin (a broad CYP inducer and an OATP1B inhibitor) on the pharmacokinetics of ABT-494 in humans.

Methods:

Two studies were conducted.  In the first study, using a randomized, two sequence, cross-over design, healthy adult subjects (N = 12) received a single dose of 3 mg ABT-494 in three different occasions: after 10 hours of fasting, 30 minutes after starting a high-fat breakfast, and on Day 4 of a 6-day regimen of  once daily ketoconazole (400 mg) under fasting condition.  In the second study, healthy adult subjects (N = 12) received single doses of 12 mg ABT-494 on three sequential occasions: alone, with the 1^st, and with the 8^thdose of a 9-day regimen of once daily rifampin (600 mg).  Serial blood samples were collected to determine ABT-494 plasma concentrations and safety and tolerability were monitored.  Pharmacokinetic parameters for ABT-494 were calculated using non-compartmental analyses. 

Results:

Relative to administration under fasting conditions, high-fat meal delayed ABT-494 T_max by approximately 1 hour, decreased ABT-494 C_max by 23% and had no impact on ABT-494 AUC.  Administration of ABT-494 with repeated doses of ketoconazole increased ABT-494 C_max and AUC by 70% and 75%, respectively.  Repeat-dose administration of rifampin decreased ABT-494 C_maxand AUC by 51% and 61%, respectively, whereas single dose co-administration of rifampin had no effect on ABT-494 AUC. ABT-494 was well tolerated by subjects.

Conclusion:

Food has no clinically meaningful effect on ABT-494 plasma exposure.  Strong inhibition of CYP3A results in a limited increase in ABT-494 exposure (i.e. weak pharmacokinetic interaction).  The broad CYP inducer rifampin reduces ABT-494 exposure by approximately half, while lack of effect of the first dose of rifampin on ABT-494 AUC suggests no interaction of ABT-494 with OATP1B inhibitors.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/assessment-of-the-effect-of-cyp3a-inhibition-cyp-induction-oatp1b-inhibition-and-administration-of-high-fat-meal-on-the-pharmacokinetics-of-the-potent-and-selective-jak1-inhibitor-abt-494/