Background/Purpose: Selective Inhibition of Bcl-2 pathway may offer clinical efficacy in Systemic Lupus Erythromatosus (SLE) by restoring apoptosis in autoreactive cells, which may lead to immune response resolution. ABT-199 is an orally bioavailable, selective Bcl-2 inhibitor currently under evaluation for treatment of SLE and several oncology indications. This work characterized the pharmacokinetics of ABT-199 in female subjects with SLE following single and multiple dosing

Methods: Single escalating oral doses (10, 30, 90, 180, 300, 500 mg or matching placebo, total 48 subjects) and multiple escalating oral doses (30, 60, 120, 240, 400, 600 mg or matching placebo, total 50 subjects) of ABT-199 were evaluated. The multiple dose evaluation consisted of two cycles each including once daily dosing under non-fasting conditions for 7 days followed by a 21 day washout period. Both evaluations followed randomized, double-blind, placebo-controlled designs (3:1 active: placebo). Serial blood samples were collected for characterization of ABT-199 pharmacokinetics.

Results: ABT-199 followed bi-exponential disposition with peak plasma concentrations observed within 4 to 8 hours post dose. Steady-state exposures were achieved within 4 days of dosing. ABT-199 exposure did not deviate significantly from dose proportionality over the evaluated dose range and the median steady-state accumulation ratio was 1.1 to 1.5. ABT-199 terminal elimination half-life ranged from 7 to 17 hours and the effective half-life, calculated based on C_max to C_trough ratio at steady state, was 9 to 11 hours. The fraction of ABT-199 dose eliminated unchanged in urine was negligible

Conclusion: ABT-199 displayed favorable pharmacokinetic profile in female subjects with SLE that warrants further clinical evaluations

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/pharmacokinetics-of-the-selective-b-cell-lymphoma-2-bcl-2-inhibitor-abt-199-in-female-subjects-with-systemic-lupus-erythromatosus/