PII-088 - THE EFFECT OF UGT INHIBITION ON THE PHARMACOKINETICS OF ECOPIPAM AND ITS METABOLITES.

V. Schmith¹, D. Graden², J. Schleyer³, A. Mahableshwarkar³, S. Wanaski⁴; ¹Schmith PK/PD Consulting LLC, Cocoa Beach, FL, USA, ²Allucent, Durham, NC, USA, ³Emalex Biosciences, Chicago, IL, USA, ⁴Paragon Biosciences, Chicago, IL, USA.

Background: Ecopipam is a potent, selective antagonist of human dopamine D1/D5 receptors, currently being investigated in Tourette Disorder. Ecopipam is mostly converted by UGT1A9 to ecopipam glucuronide, with a minor pathway by CYP3A4 to form an active metabolite (EBS-101-40853). EBS-101-40853 is also glucuronidated by UGT1A9. This study was conducted to characterize the effect of UGT inhibition on ecopipam & EBS-101-40853 PK.

Methods: An open-label, fixed sequence, drug-drug interaction (DDI) study was conducted to evaluate the effect of mefenamic acid (a specific UGT1A9 inhibitor) or divalproex sodium ER (a general UGT inhibitor) on the PK of ecopipam & its metabolites in 38 healthy subjects. Ecopipam was administered on Day 1 to all subjects. In Cohort A, 18 subjects received mefenamic acid 250 mg Q6H from Days 7-13, with ecopipam administered on Day 7. In cohort B, 20 subjects received divalproex sodium ER 1250 mg daily from Days 7-16, with ecopipam dosed on Day 10. Serial PK, safety & tolerability assessments were collected. The geometric mean ratio & 90% confidence intervals for PK parameters were determined.

Results: Concomitant administration of mefenamic acid with ecopipam resulted in a small increase (12-21%) in the Cmax of ecopipam & EBS-101-40853 & a 42-45% increase in the AUCinf of ecopipam and EBS-101-40853. Concomitant administration of divalproex sodium ER with ecopipam resulted in 40-66% increases in Cmax of ecopipam & EBS-101-40853, an 2.1x increase in AUCinf of ecopipam, & an 86% increase in AUCinf of EBS 101-40853. Ecopipam alone or in combination with UGT inhibitors was well tolerated.

Conclusion: Mefenamic acid or divalproex sodium ER inhibits ecopipam metabolism. Dose adjustments of ecopipam may be needed with co-administration.