LB-012 - EVALUATION OF THE EFFECT OF CYP3A4 AND P-GLYCOPROTEIN INHIBITION BY ITRACONAZOLE OR INDUCTION BY RIFAMPICIN ON THE PHARMACOKINETICS OF ECOPIPAM AND ITS METABOLITES

V. Schmith¹, J. Schleyer², P. Rice², T. Cunnoff³, F. Munschauer², S. Wanaski³; ¹Schmith PK/PD Consulting LLC and Syntegrity Quantitative Clinical Pharmacology Collaborative, Cocoa Beach, FL, United States, ²Emalex Biosciences, Chicago, IL, United States, ³Paragon Biosciences, Chicago, IL, United States.

Background: Ecopipam is a dopamine-1 (D1) receptor antagonist under investigation as a potential treatment for Tourette’s Syndrome (TS). Ecopipam is a P-gp substrate; 80% of ecopipam is metabolized through UGT1A9 to ecopipam glucuronide (E-G) and 10.5% is metabolized through CYP3A4 to EBS-101-40853 (EBS), which is further metabolized to EBS-glucuronide (EBS-G). The effects of P-gp or CYP3A4 inhibition or CYP3A4 induction on ecopipam have not been previously reported.

Methods: A clinical study was conducted to evaluate the PK of ecopipam and its metabolites after a single dose of ecopipam in healthy subjects in the presence and absence of itraconazole (ITZ, n=19) or rifampicin (RIF, n=26). A choice reaction time index (RTI) and visual analogue scale (VAS) were used to measure sedation. PK parameters were determined using noncompartmental analysis (NCA), with the geometric mean ratio and 90% confidence intervals determined.

Results: Ecopipam’s Cmax was 29% higher in the presence of ITZ, with no change in ecopipam’s AUC or in E-G’s Cmax or AUC. Cmax and AUC of EBS and EBS-G were 45-57% lower in the presence of ITZ. There were no substantial changes in RTI or VAS in the presence of ITZ. Ecopipam’s Cmax and AUC were 70-75% lower, EBS’ Cmax was 70% higher with no changes in EBS’ AUC, E-G’s AUC was reduced by 22%, while EBS-G’s AUC was increased by 86% in the presence of rifampicin.

Conclusion: The small effect of itraconazole on ecopipam Cmax observed is likely related to CYP3A4 inhibition and not P-gp inhibition. These results suggest that no dosage adjustments are required when ecopipam is co-administered with P-gp inhibitors or CYP3A4 inhibitors. The effect of rifampicin on decreased ecopipam concentrations is as expected when administering an inducer with a drug that is metabolized. Co-administration of ecopipam with an inducer is not recommended.