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.