Increasing Ecopipam Exposure Improves Yale Global Tic Severity Scale-Total Tic Scores (YGTSS-TTS) in Children and Adolescents with Tourette Syndrome (TS): Results from a Population Pharmacokinetic (popPK) Model-Based Simulation Using D1AMOND Trial Data
Soha Freidy1, Teodora Dumitrescu1, Virginia Schmith2, Donald Gilbert3, Atul Mahableshwarkar4, Jordan Dubow5, Timothy Cunniff5, David Kim4, Meredith Miller4, Stephen Wanaski5
1Allucent, 2Schmith PK/PD Consulting, LLC, 3Cincinnati Children's Hospital Med. Ctr., 4Emalex Biosciences, 5Paragon Biosciences
Objective:
To develop popPK and exposure-response (E-R) models to characterize the relationship between ecopipam concentrations and efficacy as well as safety in children and adolescents (ages 6 to <18 years) with TS.
Background:
Ecopipam is a first-in-class selective dopamine-1 receptor antagonist in development for TS. Results from the 12-week randomized, double-blind placebo-controlled phase 2b D1AMOND trial demonstrated 2 mg/kg/day ecopipam significantly reduced motor and phonic tics (YGTSS-TTS) and was well-tolerated. Understanding the PK of ecopipam and its active metabolite, the intrinsic/extrinsic factors affecting variability, and the relationships between exposure and efficacy/safety in TS are key to perform model-based simulations to ensure the optimal dose in TS.
Design/Methods:
In D1AMOND, a responder was defined as a >25% improvement in YGTSS-TTS. Logistic regression modeling was used to determine the relationship between responder status and exposure (area-under-the-curve, AUC) of ecopipam and its active metabolite (E+M) in children and adolescents with TS.
Results:
The steady-state (E+M) AUC exposure predicted clinical YGTSS-TTS responders at week 12. A 2-compartment model with first-order absorption and elimination described plasma concentration-time data for ecopipam and a 1-compartment model with first order elimination described the active metabolite concentration-time data. The final logistic regression model was based on the combined steady-state AUC for E+M as a univariate predictor for a clinical responder. The odds of >25% improvement in YGTSS-TTS increased near linearly by 6.8% for each 100 unit increase in E+M steady-state AUC. E-R modeling of safety parameters was not performed as there were not enough adverse events in the study to model.
Conclusions:
These data demonstrate a positive relationship between ecopipam exposure and efficacy in pediatric patients with TS. This study validates the D1AMOND trial ecopipam dosing and informed the posology for a confirmatory Phase 3 trial, currently recruiting patients.