The Effect of Uridine Diphosphate‐Glucuronosyltransferase Inhibition on the Pharmacokinetics of Ecopipam and Its Metabolites

Ecopipam, a selective dopamine D1 receptor antagonist in development for Tourette syndrome, is primarily converted by uridine diphosphate-glucuronosyltransferase (UGT)1A9 to ecopipam glucuronide, with a minor metabolic pathway by cytochrome P450 3A4 forming EBS-101-40853 (also referred to as N-desmethylecopipam or SCH 40853; also glucuronidated by UGT1A9). This open-label, fixed-sequence study evaluated the effect of mefenamic acid (UGT1A9 inhibitor) and divalproex sodium extended release (ER; general UGT inhibitor) on the pharmacokinetics (PK) of ecopipam and its metabolites. Ecopipam 179.2 mg was administered on Day 1. Cohort A received mefenamic acid 250 mg every 6 h from Days 7 to 13, with ecopipam 179.2 mg co-administered on Day 7. Cohort B received divalproex sodium ER 1250 mg once daily from Days 7 to 16, with ecopipam 179.2 mg co-administered on Day 10. A total of 38 healthy individuals (mean [SD] age, 38.2 [8.3] years; 81.6% male) had ≥ 1 post-dose safety or PK assessment, and 31 completed the study. Ecopipam alone or with UGT inhibitors was well tolerated. Mefenamic acid increased the C_max of ecopipam (21%) and EBS-101-40853 (12%) and AUC_inf of ecopipam (45%) and EBS-101-40853 (42%), but did not substantially alter the PK of ecopipam glucuronide or EBS-101-40853 glucuronide. Divalproex sodium ER increased the C_max (66%) and AUC_inf (2.1×) of ecopipam, increased the C_max (40%) and AUC_inf (86%) of EBS-101-40853, and decreased the C_max of ecopipam glucuronide and EBS-101-40853 glucuronide (23% and 32%, respectively). Inhibition of ecopipam metabolism indicated that ecopipam dose adjustments may be needed when administered with UGT inhibitors.