PI‐41

PURPOSE To characterize the pharmacodynamic activity of PRX‐00023 following single and multiple oral PRX‐00023 doses in healthy subjects. METHODS In a single ascending dose study, 36 healthy subjects received an oral dose (10 mg to 60 mg) of PRX‐00023. In addition, six subjects received a single 30 mg oral dose of Buspirone (an azapirone 5HT1A agonist). In two multiple dose studies healthy subjects received doses of 10 to 150 mg PRX‐00023 QD or placebo for up to 28 days. A Profile of Mood States (POMS) survey was administered in the 28‐day study. RESULTS Following single dose administration, mean serum prolactin peak change from baseline (13–35 ng/mL) was dose dependent up to 40 mg. In addition, prolactin response with PRX‐00023 observed was similar in magnitude but less variable than the response seen with the single 30 mg dose of buspirone. Following multiple dose administration, transient prolactin increases post dose were observed, but mean trough prolactin values were similar for placebo and the highest PRX‐00023 dose group. Trends towards beneficial effects in POMS tension/anxiety item scores were appreciated at the 40 and 60 mg PRX‐00023 doses in the 28 day study. CONCLUSIONS PRX‐00023 treatment resulted in consistent, transient induction of prolactin levels 2 to 3 hours after administration, consistent with its mechanism as a 1A agonist. This is one of the first compounds discovered by computational receptor modeling to demonstrate selective pharmacodynamic effects in humans. Clinical Pharmacology & Therapeutics (2005) 79 , P18–P18; doi: 10.1016/j.clpt.2005.12.062