Ecopipam, a Dopamine <scp>D1</scp> Receptor Antagonist: Pharmacokinetics, Mass Balance, and Metabolism in Healthy Volunteers

ABSTRACT Ecopipam is a dopamine‐1 (D1) receptor antagonist in development for Tourette syndrome. In vitro data showed that ecopipam is metabolized to ecopipam glucuronide through uridine diphosphate‐glucuronosyltransferase 1A9 and to EBS‐101‐40853 (previously called N‐desmethylecopipam or SCH 40853) through cytochrome P450 3A4. This open‐label, non‐randomized, mass balance study investigated metabolism and elimination pathways of ecopipam. A single oral dose of ecopipam 179.2 mg containing 88.5 μCi (3.27 MBq) of [ 14 C]‐labeled ecopipam was administered to 8 healthy males. Total radioactivity, ecopipam, and ecopipam metabolite concentrations were measured in blood, plasma, urine, and feces periodically until discharge (between Days 8 and 15 postdose). Pooled plasma was used to identify and quantify unknown metabolites. Overall, 83.3% of radioactivity was recovered in urine as metabolites (&lt; 1% as ecopipam), and 8.27% was excreted in feces (6.43% as ecopipam). Ecopipam glucuronide accounted for 80.0% of radioactivity in plasma and 66.9% of radioactivity in urine. EBS‐101‐40853 accounted for 10.5% of the plasma AUC ∞ for ecopipam. Geometric mean half‐lives of ecopipam, EBS‐101‐40853, and total radioactivity in plasma were 17.3, 25.6, and 94.1 h, respectively. Uncharacterized metabolites P3 and P5, ‘corrected’ for extraction efficiency, had plasma half‐lives (97.4 and 122 h, respectively) similar to total radioactivity. Unknown P3, P4, and P5 metabolites accounted for 4.62%, 0.243%, and 6.03%, respectively, of plasma radioactivity. Ecopipam is primarily metabolized to ecopipam glucuronide, with only 10.5% metabolized to EBS‐101‐40853. The long half‐life of plasma radioactivity was attributed to previously uncharacterized metabolites that each accounted for &lt; 10% of radioactivity and were considered not clinically relevant.