PII-123 - METABOLIC PROFILING OF ECOPIPAM

V. Schmith¹, S. English², A. Dymond³, C. Holdsworth³, R. Stow³, E. Holbrook³, S. Hewitt³, J. Schleyer⁴, S. Wanaski⁵; ¹Schmith PK/PD Consulting LLC, ²Pharmaron, ³Labcorp, ⁴Emalex Biosciences, ⁵Paragon Biosciences.

Background: Ecopipam is a first-in-class D1 receptor antagonist under investigation as a potential treatment for Tourette’s Disorder (TD). In vitro data in humans suggests that the major pathway of elimination of ecopipam is by direct glucuronidation with metabolism to form EBS-101-40853 (an active metabolite) accounting for 5%. This study was designed to investigate the nature of ecopipam metabolites present in plasma and excreta after a single [14C] ecopipam dose.

Methods: A single [14C] ecopipam dose was administered to 8 healthy male subjects in an open label, non-randomized study. Total radioactivity in blood, plasma, urine, and feces were measured over 336 h postdose. Ecopipam and its active metabolite (EBS-101-40853) were measured in plasma, urine, and feces over 168 h postdose. PK parameters were measured using noncompartmental analysis. Pooled plasma (overall & at specific timepoints) and urine were used to quantify and identify the analytes found in plasma and urine.

Results: 83% of radioactivity was recovered in urine ( < 1% as ecopipam or EBS-101-40853) and 8% of radioactivity was recovered in feces (6% as unchanged ecopipam). Glucuronidation to form ecopipam glucuronide accounted for 80% of radioactivity in plasma and 67% of radioactivity in urine. Metabolism to form EBS-101-40853 accounted for 10.5% of ecopipam’s AUCinf. The geometric mean t½ of ecopipam, EBS-101-40853, and total radioactivity in plasma were 17.3, 25.6, and 94 h, respectively. The t½ for the uncharacterized metabolites P3 (97.4 hours) and P5 (later identified as EBS-101-40853 sulfate; 122 hours) corrected for extraction efficiency from pooled plasma closely resembled that observed in total radioactivity. The estimated fractions of AUCinf values for P3, P4, and P5 metabolites relative to plasma total radioactivity were 0.0462, 0.00243 and 0.0603, respectively, indicating none of these metabolites accounted for >10% of the total radioactivity in plasma.

Conclusion: Ecopipam is extensively metabolized, with the metabolites mostly excreted in the urine. Glucuronidation was the primary pathway for ecopipam’s metabolism, with only 10.5% metabolized to EBS-101-40853. A long t½ of plasma radioactivity accounted for several metabolites which accounted for < 10% of radioactivity and were therefore, not clinically relevant.