Objective:

To evaluate the effect of ecopipam on cardiac repolarization (QTcF) after therapeutic or supratherapeutic doses using concentration-QTc (C-QTc) analysis.

Background:

Ecopipam is a first-in-class selective dopamine-1 receptor antagonist being investigated for treatment of Tourette’s Syndrome. Ecopipam is primarily metabolized to ecopipam glucuronide (E-G) by UGT1A9, with a minor metabolite (EBS-101-40853) formed by CYP3A4 and its glucuronide conjugate (EBS-G) by UGT1A9. 

Design/Methods:

A randomized, double-blind, placebo-controlled, 4-way crossover study with single doses of ecopipam 179.2 mg, ecopipam 537.6 mg, placebo, and open-label moxifloxacin 400 mg was conducted. Serial 12-lead ECGs collected from pre-dose to 48h post-dose were measured by central ECG laboratory using Early Precision QT analysis. C-QTc analysis was conducted to evaluate the relationship between concentrations of ecopipam, EBS-101-40853, E-G, and EBS-G and change from baseline (Δ)QTcF to exclude an effect of placebo-corrected ΔQTcF (ΔΔQTcF) of ≥10 msec at the therapeutic and the high clinical drug exposure scenario (ecopipam + general UGT inhibitors). Eight C-QTc models were performed, and a model selection procedure was utilized with pre-specified criteria.

Results:

Ecopipam did not affect heart rate, PR or QRS interval. In the C-QTc analysis, the primary model with EBS-101-40853 and ecopipam glucuronide provided the best fit to the data. An effect on ΔΔQTcF exceeding 10 msec could be excluded up to ecopipam concentrations of ~102 ng/mL, EBS-101-40853 concentrations of ~5.82 ng/mL, E-G concentrations of ~4720 ng/mL, and EBS-G of ~99.4 ng/mL, respectively. 

Conclusions:

A 10 msec increase in ΔΔQTcF can be ruled out at ecopipam 179.2 mg, the therapeutic dose. A 10 msec increase in ΔΔQTcF interval cannot be ruled out at the high clinical drug exposure (ecopipam 179.2 mg + a general UGT inhibitor), but the effect is small. After a 537.6 mg ecopipam dose, increases in the ΔΔQTcF interval up to 20.4 msec are predicted.