Drug-Drug Interaction Study to Evaluate the Effect of Inhibition of UGTs on the PK of Ecopipam and Its Active Metabolite

Study Overview
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Brief Summary
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This is a single center, open-label, fixed sequence, drug-drug interaction (DDI) study in healthy subjects.

Detailed Description
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Following a 28-day Screening period, eligible subjects will enter the clinical research unit (CRU) and will be enrolled into either Cohort A or B. Subjects in both cohorts will receive a single dose of ecopipam on Day 1. On Day 7, subjects will begin taking a UGT inhibitor according to their assigned cohort. Subjects in Cohort A will receive mefenamic acid 250 mg every 6 hours for 7 days, while subjects in Cohort B will receive divalproex sodium ER 1250 mg once a day for 10 days. A single oral dose of ecopipam will also be administered to Cohort A on Day 7, 1 hour after the first dose of mefenamic acid, and to Cohort B on Day 10, 1 hour after administration of divalproex sodium ER. Subjects in Cohort A will continue taking mefenamic acid through the evening of Day 13 and will remain in the CRU until discharged on Day 14/ET. Subjects in Cohort B will continue taking divalproex sodium ER through Day 16 and will remain in the CRU until discharge on Day 17/ET.

Official Title
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A Phase 1, Open-Label, Fixed Sequence, Drug-Drug Interaction Study to Evaluate the Effect of Inhibition of Uridine 5'-Diphosphate-glucuronosyltransferases (UGTs) on the Pharmacokinetics of Ecopipam Tablets and Its Active Metabolite (EBS-101-40853) in Healthy Subjects

Conditions
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Drug Interaction

Intervention / Treatment
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* Drug: ecopipam HCL
* Drug: Mefenamic acid
* Drug: Divalproex Sodium ER


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male subjects or female subjects of non-childbearing potential ≥18 and ≤55 years of age at the time of consent BMI >18.5 and <30 kg/m2 and a weight of ≥50 kg Sexually active males must use a double barrier method of contraception during the study and for at least 90 days after the last dose of study drug Male subjects must be willing not to donate sperm until 90 days following the last study drug administration Exclusion Criteria: Personal or family History of significant medical illness Clinically significant abnormalities on screening tests/exams History of or significant risk of committing suicide Donation of plasma within 7 days prior to dosing Donation or significant loss of blood within 30 days prior to the first dosing Major surgery within 3 months or minor surgery within 1 month prior to admission Use of prohibited prescription, over-the-counter medications or natural health products Alcohol-based products 24 hours prior to admission Female subjects who are currently pregnant or lactating Use of tobacco or nicotine products within 3 months prior to Screening Significant alcohol consumption History of drug abuse within the previous 2 years, or a positive drug screen History of allergy to study medications Not suitable for study in the opinion of the Principal Investigator

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Cohort A<br>Ecopipam HCL - 2 doses of 200mg Mefenamic acid 250mg Q6H for 7 days | Drug: ecopipam HCL<br>* oral tablets<br>Drug: Mefenamic acid<br>* oral capsules<br>|
| Other: Cohort B<br>Ecopipam HCL - 2 doses of 200mg Divalproex acid 1250mg QD for 10 days | Drug: ecopipam HCL<br>* oral tablets<br>Drug: Divalproex Sodium ER<br>* oral tablets<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cmax of ecopipam in the presence of mefenamic acid | Up to 35 blood samples will be collected at the indicated time points for pharmacokinetic analysis | Up to Day 16 | 
| Cmax of ecopipam in the absence of mefenamic acid | Up to 35 blood samples will be collected at the indicated time points for pharmacokinetic analysis | Up to Day 16 | 
| Cmax of ecopipam in the presence of divalproex sodium ER | Up to 35 blood samples will be collected at the indicated time points for pharmacokinetic analysis | Up to Day 16 | 
| Cmax of ecopipam in the absence of divalproex sodium ER | Up to 35 blood samples will be collected at the indicated time points for pharmacokinetic analysis | Up to Day 16 | 
| AUCinf of ecopipam in the presence of mefenamic acid | Up to 35 blood samples will be collected at the indicated time points for pharmacokinetic analysis | Up to Day 16 | 
| AUCinf of ecopipam in the absence of mefenamic acid | Up to 35 blood samples will be collected at the indicated time points for pharmacokinetic analysis | Up to Day 16 | 
| AUCinf of ecopipam in the presence of divalproex sodium ER | Up to 35 blood samples will be collected at the indicated time points for pharmacokinetic analysis | Up to Day 16 | 
| AUCinf of ecopipam in the absence of divalproex sodium ER | Up to 35 blood samples will be collected at the indicated time points for pharmacokinetic analysis | Up to Day 16 | 
| AUC0-143 of ecopipam in the presence of mefenamic acid | Up to 35 blood samples will be collected at the indicated time points for pharmacokinetic analysis | Up to Day 16 | 
| AUC0-143 of ecopipam in the absence of mefenamic acid | Up to 35 blood samples will be collected at the indicated time points for pharmacokinetic analysis | Up to Day 16 | 
| AUC0-143 of ecopipam in the presence of divalproex sodium ER | Up to 35 blood samples will be collected at the indicated time points for pharmacokinetic analysis | Up to Day 16 | 
| AUC0-143 of ecopipam in the absence of divalproex sodium ER | Up to 35 blood samples will be collected at the indicated time points for pharmacokinetic analysis | Up to Day 16 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cmax of EBS-101-40853 | Up to 35 blood samples will be collected at the indicated time points for pharmacokinetic analysis | Up to Day 16 | 
| AUCinf of EBS-101-40853 | Up to 35 blood samples will be collected at the indicated time points for pharmacokinetic analysis | Up to Day 16 | 
| AUC0-143 of EBS-101-40853 | Up to 35 blood samples will be collected at the indicated time points for pharmacokinetic analysis | Up to Day 16 | 
| Cmax of mefenamic acid | Up to 15 blood samples will be collected at the indicated time points for pharmacokinetic analysis | Up to Day 16 | 
| Tmax of mefenamic acid | Up to 15 blood samples will be collected at the indicated time points for pharmacokinetic analysis | Up to Day 16 | 
| AUCtau of mefenamic acid | Up to 15 blood samples will be collected at the indicated time points for pharmacokinetic analysis | Up to Day 16 | 
| t½ of mefenamic acid | Up to 15 blood samples will be collected at the indicated time points for pharmacokinetic analysis | Up to Day 16 | 
| Cmax of VPA | Up to 19 blood samples will be collected at the indicated time points for pharmacokinetic analysis | Up to Day 16 | 
| Tmax of VPA | Up to 19 blood samples will be collected at the indicated time points for pharmacokinetic analysis | Up to Day 16 | 
| AUCtau of VPA | Up to 19 blood samples will be collected at the indicated time points for pharmacokinetic analysis | Up to Day 16 | 
| Safety and tolerability as demonstrated by MOAA/S | Safety and tolerability measures will be recorded at the indicated timepoints. | Up to Day 17 | 
| Safety and tolerability as demonstrated by C-SSRS | Safety and tolerability measures will be recorded at the indicated timepoints. | Up to Day 17 | 
| Safety and tolerability as demonstrated by concomitant medications | Safety and tolerability measures will be recorded at the indicated timepoints. | Up to Day 42 | 
| AEs with relatedness associated with mefenamic acid | Subjects will be continually monitored for adverse events | Up to Day 42 | 
| AEs with relatedness associated with divalproex sodium ER | Subjects will be continually monitored for adverse events | Up to Day 42 | 
| AEs with relatedness associated with ecopipam | Subjects will be continually monitored for adverse events | Up to Day 42 | 
| Absolute values of white blood cell (WBC) count (K/Ul) | Blood samples will be collected for the assessment of hematology parameters. | Up to Day 17 | 
| Absolute values of neutrophils, lymphocytes, monocytes, eosinophils, and basophils (10E3/uL) | Blood samples will be collected for the assessment of hematology parameters. | Up to Day 17 | 
| Absolute values of platelets (K/uL) | Blood samples will be collected for the assessment of hematology parameters. | Up to Day 17 | 
| Absolute values of hematocrit (%) | Blood samples will be collected for the assessment of hematology parameters. | Up to Day 17 | 
| Absolute values of hemoglobin (g/dL) | Blood samples will be collected for the assessment of hematology parameters. | Up to Day 17 | 
| Absolute values of Red blood cell (RBC) count (M/uL) | Blood samples will be collected for the assessment of hematology parameters. | Up to Day 17 | 
| Absolute values of blood sodium, magnesium, urea, phosphorus, potassium, and chloride (mg/dL) | Blood samples will be collected for the assessment of clinical chemistry parameters. | Up to Day 17 | 
| Absolute values of creatinine, calcium, glucose, and direct and total bilirubin (mg/dL) | Blood samples will be collected for the assessment of clinical chemistry parameters. | Up to Day 17 | 
| Absolute values of albumin and total protein (g/dL) | Blood samples will be collected for the assessment of clinical chemistry parameters. | Up to Day 17 | 
| Absolute values of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), gamma glutamyl transferase (GGT), and creatinine phosphokinase (CPK) | Blood samples will be collected for the assessment of clinical chemistry parameters. | Up to Day 17 | 
| Absolute values of urine specific gravity | Urine samples will be collected for the assessment of urine parameters. | Up to Day 17 | 
| Absolute values of urine pH | Urine samples will be collected for the assessment of urine parameters. | Up to Day 17 | 
| Absolute values of urine glucose | Urine samples will be collected for the assessment of urine parameters. | Up to Day 17 | 
| Absolute values of urine protein | Urine samples will be collected for the assessment of urine parameters. | Up to Day 17 | 
| Absolute values of urine blood | Urine samples will be collected for the assessment of urine parameters. | Up to Day 17 | 
| Absolute values of urine ketones | Urine samples will be collected for the assessment of urine parameters. | Up to Day 17 | 
| Absolute values of urine bilirubin, urobilinogen, and nitrite | Urine samples will be collected for the assessment of urine parameters. | Up to Day 17 | 
| Absolute values of urine leukocytes by dipstick | Urine samples will be collected for the assessment of urine parameters. | Up to Day 17 | 
| Change from Day -1 to Day of Discharge in white blood cell (WBC) count (K/Ul) | Blood samples will be collected for the assessment of hematology parameters. | Up to Day 17 | 
| Change from Day -1 to Day of Discharge in neutrophils, lymphocytes, monocytes, eosinophils, and basophils (10E3/uL) | Blood samples will be collected for the assessment of hematology parameters. | Up to Day 17 | 
| Change from Day -1 to Day of Discharge in platelets (K/uL) | Blood samples will be collected for the assessment of hematology parameters. | Up to Day 17 | 
| Change from Day -1 to Day of Discharge in hematocrit (%) | Blood samples will be collected for the assessment of hematology parameters. | Up to Day 17 | 
| Change from Day -1 to Day of Discharge in hemoglobin (g/dL) | Blood samples will be collected for the assessment of hematology parameters. | Up to Day 17 | 
| Change from Day -1 to Day of Discharge in Red blood cell (RBC) count (M/uL) | Blood samples will be collected for the assessment of hematology parameters. | Up to Day 17 | 
| Change from Day -1 to Day of Discharge in blood sodium, magnesium, urea, phosphorus, potassium, and chloride (mg/dL) | Blood samples will be collected for the assessment of clinical chemistry parameters. | Up to Day 17 | 
| Change from Day -1 to Day of Discharge in creatinine, calcium, glucose, and direct and total bilirubin (mg/dL) | Blood samples will be collected for the assessment of clinical chemistry parameters. | Up to Day 17 | 
| Change from Day -1 to Day of Discharge in albumin and total protein (g/dL) | Blood samples will be collected for the assessment of clinical chemistry parameters. | Up to Day 17 | 
| Change from Day -1 to Day of Discharge in alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), gamma glutamyl transferase (GGT), and creatinine phosphokinase (CPK) (U/L) | Blood samples will be collected for the assessment of clinical chemistry parameters. | Up to Day 17 | 
| Change from Day -1 to Day of Discharge in urine specific gravity | Urine samples will be collected for the assessment of urine parameters. | Up to Day 17 | 
| Change from Day -1 to Day of Discharge in urine pH | Urine samples will be collected for the assessment of urine parameters. | Up to Day 17 | 
| Change from Day -1 to Day of Discharge in urine glucose | Urine samples will be collected for the assessment of urine parameters. | Up to Day 17 | 
| Change from Day -1 to Day of Discharge in urine protein | Urine samples will be collected for the assessment of urine parameters. | Up to Day 17 | 
| Change from Day -1 to Day of Discharge in urine blood | Urine samples will be collected for the assessment of urine parameters. | Up to Day 17 | 
| Change from Day -1 to Day of Discharge in urine ketones | Urine samples will be collected for the assessment of urine parameters. | Up to Day 17 | 
| Change from Day -1 to Day of Discharge in urine bilirubin, urobilinogen, and nitrite (Milligrams per deciliter) | Urine samples will be collected for the assessment of urine parameters. | Up to Day 17 | 
| Change from Day -1 to Day of Discharge in urine leukocytes by dipstick | Urine samples will be collected for the assessment of urine parameters. | Up to Day 17 | 
| Change from Day 6 to Day of Discharge in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) (U/L) | Blood samples will be collected for the assessment of clinical chemistry parameters. | Up to Day 17 | 
| Absolute values of electrocardiogram (ECG) parameters: PR, QRS, QT, and QT interval corrected for heart rate using Fridericia's formula (QTcF) (Milliseconds) | Twelve-lead ECGs will be obtained with the participant in a supine position after a rest of at least 5 minutes using an automated ECG machine. PR, QRS, QT, and QTcF intervals will be measured. | Up to Day 10 | 
| Change from pre-dose for the respective day in ECG parameters: PR, QRS, QT, and QTcF (Milliseconds) | Twelve-lead ECGs will be obtained with the participant in a supine position after a rest of at least 5 minutes using an automated ECG machine. PR, QRS, QT, and QTcF intervals will be measured. | Up to Day 10 | 
| Absolute values of oral temperature (degrees Celsius) | Temperature will be assessed as part of vital signs. | Up to Day 17 | 
| Change from pre-dose for the respective day in oral temperature (degrees Celsius) | Temperature will be assessed as part of vital signs. | Up to Day 17 | 
| Absolute values of heart rate (beats/minute) | Heart rate will be assessed as part of vital signs. | Up to Day 17 | 
| Change from pre-dose for the respective day in heart rate (beats/minute) | Heart rate will be assessed as part of vital signs. | Up to Day 17 | 
| Absolute values of respiratory rate (breaths/minute) | Respiratory rate will be assessed as part of vital signs. | Up to Day 17 | 
| Change from pre-dose for the respective day in respiratory rate (breaths/minute) | Respiratory rate will be assessed as part of vital signs. | Up to Day 17 | 
| Absolute values of systolic blood pressure (SBP) and diastolic blood pressure (DBP) (mmHG) | Blood pressure will be assessed as part of vital signs. | Up to Day 17 | 
| Change from pre-dose for the respective day in SBP and DBP (mmHG) | Blood pressure will be assessed as part of vital signs. | Up to Day 17 |