Abstract Details

Title The Effect of Ecopipam and its Metabolites on Cardiac Repolarization, QTcF

Topic Movement Disorders

Presentation(s) P10 - Poster Session 10 (5:00 PM-6:00 PM)

Poster/Presentation
Number 5-014

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.

Authors/Disclosures
Stephen Wanaski, PhD (Paragon Biosciences) PRESENTER	Dr. Wanaski has received personal compensation for serving as an employee of Paragon Biosciences. Dr. Wanaski has or had stock in Paragon Biosciences.Dr. Wanaski has or had stock in Emalex Biosciences.
Hongqi Xue, PhD	Dr. Xue has nothing to disclose.
Borje B. Darpo, MD, PhD	Dr. Darpo has stock in Clario.
Joy Schleyer (Emaxlex Biosciences)	Joy Schleyer has received personal compensation for serving as an employee of Emalex Biosciences.
Timothy Cunniff, PharmD	Dr. Cunniff has received personal compensation for serving as an employee of Paragon Biosciences. Dr. Cunniff has stock in Harmony Biosciences. Dr. Cunniff has stock in Emalex Biosciences.
Frederick E. Munschauer III, MD, FAAN (FEMC)	Dr. Munschauer has received personal compensation for serving as an employee of Emalex Biosciences. Dr. Munschauer has stock in Emalex Biosciences.
Patricia Rice (Emaxlex Biosciences)	Patricia Rice has received personal compensation for serving as an employee of Emalex Biosciences.
Virginia Schmith, PhD	Dr. Schmith has received personal compensation in the range of $100,000-$499,999 for serving as a Consultant for Emalex Biosciences.

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