(M0930-05-32) Nonparametric Superposition and Simulation to Predict Recommended Dosing of Ecopipam for Patients with Various Degrees of Chronic Hepatic Insufficiency

Purpose: A previously reported hepatic impairment study conducted prior to 2000 evaluated the pharmacokinetics (PK) and safety of ecopipam and its active metabolite (EBS-101-40853) after a single dose of 89.6 or 44.8 mg ecopipam to patients with varying degrees of hepatic impairment and healthy adult subjects. The analysis was updated to account for differences in the hepatic impairment FDA guidance and using the current Child-Pugh score. These analyses focus on the relationship between hepatic impairment characteristics and the variability in ecopipam PK parameters and adding simulation to identify whether dosage adjustments are required in patients with hepatic impairment to achieve comparable systemic exposure as subjects with normal hepatic function. A previous mass balance study showed ecopipam glucuronide represents ~80% of the radioactivity in plasma; thus, the measured total ecopipam essentially represents ecopipam glucuronide. Likewise, total EBS-101-40853 represents mostly EBS-101-40853 glucuronide.

Methods: A phase 1, open-label, single-dose, parallel-group study to evaluate the PK of ecopipam in subjects with normal hepatic function (n=5), mild hepatic impairment (n=7), moderate hepatic impairment (n=8), or severe hepatic impairment (n=1). PK parameters were calculated using noncompartmental analysis for unconjugated and total (conjugated + unconjugated) ecopipam (with mostly represents ecopipam glucuronide) and unconjugated and total EBS-101-40853 (with mostly represents EBS-101-40853 glucuronide). The relationship between hepatic function (e.g., Child Pugh score, MELD, total bilirubin, ascites) and ecopipam or metabolite exposure parameters was evaluated. Nonparametric superposition was conducted for each subject (with an adequately determined t½) to predict the plasma concentration-time profile of ecopipam after steady-state dosing. Finally, simulations (n=1000) were conducted to target a similar exposure to subjects with normal hepatic function receiving ecopipam 1.8 mg/kg daily using a clinical weight-based dosing paradigm.

Results: The ecopipam AUC_inf was ~2.2 and ~3x higher in subjects with mild and moderate hepatic impairment, respectively, relative to subjects with normal hepatic function. There was no relationship between Child-Pugh score, alanine aminotransferase, aspartate aminotransferase, or baseline sodium and ecopipam’s or total ecopipam’s dose-normalized (DN)-AUC_inf. Ecopipam DN-AUC_inf generally increased (R²>0.25) with increasing Modified MELD Score, total bilirubin, or in patients with slight ascites while it decreased with increasing albumin. There was no relationship between MELD, total bilirubin, or the presence of slight ascites and total ecopipam DN-AUC∞. Because EBS-101-40853 was not formed in subjects with moderate or severe hepatic impairment, the relationship between its exposure and covariates in hepatic impairment could not be assessed. The t½ values of ecopipam were 45% and 55% longer in mild and moderate impairment, respectively, and slightly longer than the dosing interval. Steady-state simulations showed that reducing the ecopipam 1.8 mg/kg dose to 0.9 mg/kg every day achieves a similar AUC and a lower C_max in subjects with mild or moderate hepatic impairment, relative to subjects with normal hepatic function.

Conclusion: Based on simulations of steady-state dosing with ecopipam using the clinical weight-based dosing paradigm, the daily dose of ecopipam should be reduced by 50% in patients with mild or moderate hepatic impairment. Ecopipam will be contraindicated in subjects with severe hepatic impairment.