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. Single dose PK and safety of ABT-436 were evaluated in three Phase I studies.
METHODS: Single doses of 40-1000 mg were evaluated in a randomized, double-blind, placebo-controlled, 3-period rising dose crossover study with 2 groups (n=9/group, 6 active + 3 placebo/period). Single doses of 1300 and 1600 mg were evaluated in a randomized, double-blind, placebo-controlled study with 2 groups (n=8/group, 6 active + 2 placebo). Food effect and KTZ interaction were studied for a single 200 mg dose using an open-label, 3-period, randomized, crossover design in 12 subjects. The first 2 periods evaluated food effect. In the third period, subjects received ABT-436 on Day 4 with 400 mg KTZ (QD, Days 1 to 8). Intensive PK samples were collected. Safety and tolerability were assessed throughout each study.
RESULTS: ABT-436 PK was linear over the 150-1600 mg dose range with half-life of 25-28 hr. At 40 mg, exposures were less than dose proportional. Food had minimal impact (<20%) on ABT-436 exposure. KTZ increased ABT-436 exposures 2.4-(Cmax) and 4.1-(AUC) fold. No clinically significant measurement on vital signs, ECG or laboratory variables or trends was observed during the studies. Mild gastrointestinal adverse events were more prevalent at 1300 mg and 1600 mg dose, with a trend for increasing prevalence with dose. A maximum tolerated ABT-436 dose was not identified.
CONCLUSION: ABT-436 PK profile supports once-daily dosing and can be taken without regard to food. ABT-436 showed a moderate interaction with ketoconazole. The results of these studies support further evaluation of ABT-436 in a wide dose range.