Background/Purpose: ABT-494 is a selective Janus Kinase 1 inhibitor. In two Phase 2b studies in subjects with rheumatoid arthritis, 6 mg and 12 mg twice-daily (BID) doses of ABT-494 immediate-release formulation achieved optimal benefit-risk profiles. To enhance patients’ compliance, an extended-release formulation was developed targeting to achieve comparable exposures with the 6 mg and 12 mg BID of the immediate-release formulation with once-daily (QD) administration. This work characterized the pharmacokinetics of ABT-494 with the extended-release formulation that is currently being utilized in Phase 3.

Methods:

Comparison of ABT-494 pharmacokinetics from the immediate-release and extended-release formulations was conducted following multiple-dose administration in healthy subjects. Two cohorts of subjects were evaluated. In the first cohort, healthy subjects (N = 12) received multiple 15 mg QD doses of the extended-release tablet formulation and multiple 6 mg BID doses of the immediate-release capsule formulation for 7 days. In the second cohort, healthy subjects (N = 12) received multiple 30 mg QD doses of the extended-release tablet formulation and multiple 12 mg BID doses of the immediate-release capsule formulation for 7 days. Both evaluations were conducted following an open-label, randomized, 2-period, 2-sequence, crossover design under fasting conditions. ABT-494 plasma concentrations were measured and pharmacokinetic parameters were calculated using non-compartmental analyses.

Results: At steady-state, ABT-494 AUC_0-24 ratio [and 90% confidence interval] was 0.94 [0.84 – 1.05], C_max ratio was 0.91 [0.74 – 1.12] and C_min ratio was 1.09 [0.85 – 1.40] for the 15 mg QD regimen of the extended-release formulation relative to the 6 mg BID regimen of the immediate-release formulation. Similarly, ABT-494 mean AUC_0-24 ratio was 0.97 [0.87 – 1.09], C_max ratio was 0.90 [0.73 – 1.11] and C_min ratio was 0.87 [0.75 – 1.02] for the 30 mg QD regimen of the extended-release formulation relative to the 12 mg BID regimen. All evaluated regimens were well-tolerated by healthy subjects.

Conclusion:  ABT-494 regimens of 15 mg QD and 30 mg QD of the extended-release formulation, currently being utilized in Phase 3 RA studies, provide similar exposures to 6 mg BID and 12 mg BID, respectively of the immediate-release capsule formulation previously shown to provide optimal benefit-risk profiles in RA Phase 2 trials.

« Back to 2016 ACR/ARHP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/pharmacokinetics-of-abt-494-with-the-once-daily-extended-release-tablet-formulation-being-utilized-in-the-ongoing-rheumatoid-arthritis-phase-3-trials/