PII-098

W. Liu,1 D. A. Katz,2 K. Tracy,2 C. Locke,1 W. M. Awni,1 S. Dutta1; 1AbbVie, North Chicago, IL, 2Former AbbVie employee, North Chicago, IL

BACKGROUND: ABT-436 is a potent V1B receptor antagonist with potential to treat major depressive disorder, anxiety disorders, and substance use disorders. Multiple-dose PK and safety were evaluated in three Phase I studies.
METHODS: Multiple ascending doses of ABT-436 were evaluated in 2 studies using a randomized, double-blind, placebo-controlled designs (6 active + 3 placebo/group for 100, 500 and 800 mg QD; 9 active + 4 placebo/group for 1100 mg and 1500 mg QD; 6 active + 6 placebo for 400 mg BID). Dosing duration was 7 (100, 500 mg QD; 400 mg BID) or 14 (800, 1100, 1500 mg QD) days. Chronopharmacokinetics was evaluated in a randomized, double-blind, placebo-controlled, 2-period study (N = 20) with 200 mg QD administered either in the morning or evening for 7 days in each period. Intensive PK samples were collected. Safety and tolerability were assessed throughout each study.
RESULTS: ABT-436 exposure increased more than dose proportionally between 100-500 mg QD range and less than dose proportionally between 500-1500 mg QD with a half-life of 30 hr and minimal urinary excretion (1-3%). Steady state was achieved by Day 6 (BID) or Day 7 (QD). ABT-436 exposures after evening dosing were significantly lower (62-77%) than with morning dosing at 200 mg QD; the difference became smaller at 400 mg BID. A dose-dependent incidence of gastrointestinal adverse events (mainly diarrhea) was observed following ABT-436 dosing. A maximum tolerated dose was not identified.
CONCLUSION: ABT-436 PK profile supports QD or BID dosing. Evening dosing was associated with lower ABT-436 exposures, with a larger difference at 200 mg compared to 400 mg. The results of these studies support further evaluation of ABT-436 in a wide dose range.