The Effect of Ecopipam on the Pharmacokinetics of Concomitant Medications

Ecopipam is a first-in-class dopamine D1 receptor antagonist under investigation for the treatment of Tourette syndrome. This open-label, fixed-sequence, three-cohort study evaluated whether ecopipam induces or inhibits cytochrome P450 (CYP) 1A2, CYP2B6, CYP2C19, CYP2D6, CYP3A4, organic anion-transporting polypeptide (OATP) 1B1, and p-glycoprotein (P-gp). Probe substrates were administered alone and after single or steady-state dosing of ecopipam (1.8 mg/kg/day). Cohort 1 received standard doses of omeprazole (CYP2C19), caffeine (CYP1A2), and dextromethorphan (CYP2D6) orally, and a microdose of midazolam (CYP3A4) intravenously. Cohort 2 received a standard dose of bupropion (CYP2B6) orally. Cohort 3 received an oral solution containing microdoses of dabigatran (P-gp), pitavastatin (OATP1B1), rosuvastatin (BCRP, OATP, and P-gp), atorvastatin (BCRP, OATP, P-gp, and CYP3A4), and midazolam. A total of 56 healthy individuals (median [range] age, 36.5 [19-54] years; 85.7% male) were enrolled, and 48 completed the study. Ecopipam was well tolerated in the presence and absence of probe substrates. Steady-state ecopipam administration increased dextromethorphan exposure (> 100-fold); decreased the AUC_inf of midazolam, omeprazole, and dabigatran by 44.2%, 44.1%, and 37.9%, respectively; and decreased unconjugated bilirubin (UGT1A1) by 19.5%. Single-dose ecopipam increased atorvastatin C_max by 95% and rosuvastatin C_max by 11%, whereas steady-state ecopipam decreased the AUC_inf of atorvastatin by 26.8% and rosuvastatin by 16.4%. There were no changes in caffeine, bupropion, or pitavastatin exposure. Ecopipam is a strong inhibitor of CYP2D6 and weak inducer of CYP3A4, CYP2C19, P-gp, and UGT1A1. Ecopipam did not inhibit CYP3A4, CYP2C19, CYP2B6, CYP1A2, UGT1A1, P-gp, or OATP1B1 and did not induce OATP1B1 or CYP2B6.