PII-125 - MICRODOSING APPROACH TO EVALUATE WHETHER ECOPIPAM AFFECTS DRUG METABOLISM AND TRANSPORT OF CONCOMITANT MEDICATIONS

V. Schmith¹, D. Graden², L. Lohmer³, J. Schleyer⁴, S. Wanaski⁵; ¹Schmith PK/PD Consulting LLC, ²Allucent, ³formerly Allucent, ⁴Emalex Biosciences, ⁵Paragon Biosciences.

Background: Ecopipam is a first-in-class dopamine D1 receptor antagonist under investigation as a potential treatment for Tourette’s Disorder (TD). In vitro data suggested that a clinical study was necessary to evaluate induction of CYP3A4, CYP1A2, CYP2B6, and P-gp and inhibition of CYP2D6, CYP3A4, P-gp, and OATP1B1 by ecopipam and its active metabolite EBS-101-40853. Because the mechanism of induction with CYP3A4 is similar to that for CYP2C and UGT, substrates for CYP2C19 and UGT1A1 were also considered. A microdose probe cocktail approach was used to evaluate multiple substrates without toxicity and drug interactions amongst substrates.

Methods: An open label, fixed sequence 3 cohort study was conducted in 56 healthy subjects where ecopipam HCl 2 mg/kg was administered daily to steady state after titration. Probe substrates were administered alone, after a single dose of 200 mg (Cohort 3 only), and after ecopipam steady-state dosing. Cohort 1 studied clinical doses of dextromethorphan (DM; CYP2D6), caffeine (CYP1A2), and omeprazole (CYP2C19) orally and microdoses of midazolam (MZ, IV; CYP3A4). Cohort 2 studied bupropion (BUP; CYP2B6). Cohort 3 studied microdoses of dabigatran (DAB; P-gp), pitavastatin (PIT; OATP1B1), rosuvastatin (ROS; BCRP, OATP, and P-gp), atorvastatin (ATOR; BCRP, OATP, P-gp, and CYP3A4), and MZ (oral; CYP3A4); endogenous direct, indirect, and total bilirubin (UGT1A1) were measured. Ecopipam was then tapered.

Results: Steady-state ecopipam administration increased DM exposure (134x), decreased MZ, omeprazole, and DAB exposure by 38-44%, and decreased bilirubin by 19%. There were no changes in caffeine, BUP, or PIT exposures. Single dose ecopipam increased ATOR by 95% and steady-state ecopipam decreased ATOR by 27%. Single dose ecopipam increased ROS by 7% and steady-state ecopipam decreased ROS exposure by 16%

Conclusion: Ecopipam is a potent inhibitor of CYP2D6, but does not inhibit CYP3A4, CYP2B6, CYP1A2, CYP2C19, UGT1A1, P-gp, or OATP1B1. Ecopipam is a moderate inducer of CYP3A4, CYP2C19, and P-gp, and weak inducer of UGT1A1, but does not induce OATP1B1, CYP1A2, or CYP2B6. Microdosing allowed an efficient evaluation of how ecopipam may affect concomitant medications