A Phase 1, Open-Label, Fixed Sequence Drug-Drug Interaction Study to Evaluate the Effects of Repeat Doses of Ecopipam on the Pharmacokinetics of Multiple Substrates for Drug Metabolism and Transport in Healthy Subjects
Overview
- Phase
- Phase 1
- Intervention
- ecopipam HCl ~2mg/kg/day
- Conditions
- Drug-Interactions
- Sponsor
- Emalex Biosciences Inc.
- Enrollment
- 30
- Locations
- 1
- Primary Endpoint
- Cmax of dextromethorphan (and its dextrorphan metabolite) in the presence of ecopipam
- Status
- Terminated
- Last Updated
- 4 years ago
Overview
Brief Summary
This is a single center, open-label, fixed sequence Phase 1, drug-drug interaction (DDI) study in healthy subjects.
Detailed Description
Following a screening period of up to 28 days, subjects will be admitted to the clinical research unit into one of three cohorts. On the morning of Day 1, subjects in cohorts 1, 2, and 3 will receive fasted doses of probe substrate(s) per assigned cohort. On Day 5, Cohort 2 only will receive a second fasted dose of probe substrates. Subjects in cohorts 1, 2, and 3 will receive the final fasted dose of probe substrate(s) on Day 13. Fasted ecopipam administration will begin on Day 5 and will continue through Day 17 at \~2mg/kg for all cohorts. Ecopipam doses will be tapered starting on Day 18 by 25 mg/day increments until subjects are off drug, with final discharge occurring 24 hours after the ecopipam HCl dose has been reduced to 25 mg (Day 21, 23, or 25).
Investigators
Eligibility Criteria
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 for males or ≥45 kg for females
- •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
- •Positive pregnancy test
Arms & Interventions
Cohort 1
ecopipam HCl oral tablets of 12.5, 50, 75, and 100 mg daily for up to 20 days Cohort 1 Probe Cocktail given on 2 separate days: * midazolam: 1 µg infused IV * caffeine: 200 mg oral tablet * omeprazole: two 20 mg oral tablets * dextromethorphan: 1.6mL (containing \~10 mg) oral solution
Intervention: ecopipam HCl ~2mg/kg/day
Cohort 1
ecopipam HCl oral tablets of 12.5, 50, 75, and 100 mg daily for up to 20 days Cohort 1 Probe Cocktail given on 2 separate days: * midazolam: 1 µg infused IV * caffeine: 200 mg oral tablet * omeprazole: two 20 mg oral tablets * dextromethorphan: 1.6mL (containing \~10 mg) oral solution
Intervention: Cohort 1 Probe Cocktail
Cohort 2
ecopipam HCl oral tablets of 12.5, 50, 75, and 100 mg daily for up to 20 days Cohort 2 Probe Cocktail given on 3 separate days: * midazolam: 10 µg/mL given as 1mL oral solution. * dabigatran: 375 µg/mL and pitavastatin: 10 µg/mL given as 1mL oral solution * rosuvastatin: 25 µg/mL and atorvastatin: 50 µg/mL given as 2mL oral solution
Intervention: ecopipam HCl ~2mg/kg/day
Cohort 2
ecopipam HCl oral tablets of 12.5, 50, 75, and 100 mg daily for up to 20 days Cohort 2 Probe Cocktail given on 3 separate days: * midazolam: 10 µg/mL given as 1mL oral solution. * dabigatran: 375 µg/mL and pitavastatin: 10 µg/mL given as 1mL oral solution * rosuvastatin: 25 µg/mL and atorvastatin: 50 µg/mL given as 2mL oral solution
Intervention: Cohort 2 Probe Cocktail
Cohort 3
ecopipam HCl oral tablets of 12.5, 50, 75, and 100 mg daily for up to 20 days Cohort 3 Probe Cocktail given on 2 separate days: - bupropion: 100mg oral tablet
Intervention: ecopipam HCl ~2mg/kg/day
Cohort 3
ecopipam HCl oral tablets of 12.5, 50, 75, and 100 mg daily for up to 20 days Cohort 3 Probe Cocktail given on 2 separate days: - bupropion: 100mg oral tablet
Intervention: Cohort 3 Probe Cocktail
Outcomes
Primary Outcomes
Cmax of dextromethorphan (and its dextrorphan metabolite) in the presence of ecopipam
Time Frame: Up to Day 18
Up to 38 blood samples will be collected at the indicated time points for pharmacokinetic analysis
Cmax of atorvastatin (and its 4'-hydroxy atorvastatin metabolite) in the absence of ecopipam
Time Frame: Up to Day 18
Up to 38 blood samples will be collected at the indicated time points for pharmacokinetic analysis
Cmax of dextromethorphan (and its dextrorphan metabolite) in the absence of ecopipam
Time Frame: Up to Day 18
Up to 38 blood samples will be collected at the indicated time points for pharmacokinetic analysis
Cmax of IV midazolam (and its 1'-hydroxymidazolam metabolite) in the absence of ecopipam
Time Frame: Up to Day 18
Up to 38 blood samples will be collected at the indicated time points for pharmacokinetic analysis
Cmax of pitavastatin (and its pitavastatin lactone metabolite) in the presence of ecopipam
Time Frame: Up to Day 18
Up to 38 blood samples will be collected at the indicated time points for pharmacokinetic analysis
Cmax of IV midazolam (and its 1'-hydroxymidazolam metabolite) in the presence of ecopipam
Time Frame: Up to Day 18
Up to 38 blood samples will be collected at the indicated time points for pharmacokinetic analysis
Cmax of oral midazolam (and its 1'-hydroxymidazolam metabolite) in the presence of ecopipam
Time Frame: Up to Day 18
Up to 38 blood samples will be collected at the indicated time points for pharmacokinetic analysis
Cmax of dabigatran in the presence of ecopipam
Time Frame: Up to Day 18
Up to 38 blood samples will be collected at the indicated time points for pharmacokinetic analysis
Cmax of dabigatran in the absence of ecopipam
Time Frame: Up to Day 18
Up to 38 blood samples will be collected at the indicated time points for pharmacokinetic analysis
Cmax of rosuvastatin in the presence of ecopipam
Time Frame: Up to Day 18
Up to 38 blood samples will be collected at the indicated time points for pharmacokinetic analysis
Cmax oral midazolam (and its 1'-hydroxymidazolam metabolite) in the absence of ecopipam
Time Frame: Up to Day 18
Up to 38 blood samples will be collected at the indicated time points for pharmacokinetic analysis
AUCinf of oral midazolam (and its 1'-hydroxymidazolam metabolite) in the presence of ecopipam
Time Frame: Up to Day 18
Up to 38 blood samples will be collected at the indicated time points for pharmacokinetic analysis
AUCinf of oral midazolam (and its 1'-hydroxymidazolam metabolite) in the absence of ecopipam
Time Frame: Up to Day 18
Up to 38 blood samples will be collected at the indicated time points for pharmacokinetic analysis
AUCinf of dabigatran in the presence of ecopipam
Time Frame: Up to Day 18
Up to 38 blood samples will be collected at the indicated time points for pharmacokinetic analysis
AUCinf of dabigatran in the absence of ecopipam
Time Frame: Up to Day 18
Up to 38 blood samples will be collected at the indicated time points for pharmacokinetic analysis
AUCinf of pitavastatin (and its pitavastatin lactone metabolite) in the presence of ecopipam
Time Frame: Up to Day 18
Up to 38 blood samples will be collected at the indicated time points for pharmacokinetic analysis
AUCinf of pitavastatin (and its pitavastatin lactone metabolite) in the absence of ecopipam
Time Frame: Up to Day 18
Up to 38 blood samples will be collected at the indicated time points for pharmacokinetic
AUCinf of rosuvastatin in the presence of ecopipam
Time Frame: Up to Day 18
Up to 38 blood samples will be collected at the indicated time points for pharmacokinetic
AUCinf of rosuvastatin in the absence of ecopipam
Time Frame: Up to Day 18
Up to 38 blood samples will be collected at the indicated time points for pharmacokinetic
AUCinf of atorvastatin (and its 4'-hydroxy atorvastatin metabolite) in the presence of ecopipam
Time Frame: Up to Day 18
Up to 38 blood samples will be collected at the indicated time points for pharmacokinetic
AUCinf of IV midazolam (and its 1'-hydroxymidazolam metabolite) in the presence of ecopipam
Time Frame: Up to Day 18
Up to 38 blood samples will be collected at the indicated time points for pharmacokinetic analysis
AUCinf of atorvastatin (and its 4'-hydroxy atorvastatin metabolite) in the absence of ecopipam
Time Frame: Up to Day 18
Up to 38 blood samples will be collected at the indicated time points for pharmacokinetic
AUClast of dextromethorphan (and its dextrorphan metabolite) in the presence of ecopipam
Time Frame: Up to Day 18
Up to 38 blood samples will be collected at the indicated time points for pharmacokinetic
AUClast of dextromethorphan (and its dextrorphan metabolite) in the absence of ecopipam
Time Frame: Up to Day 18
Up to 38 blood samples will be collected at the indicated time points for pharmacokinetic
AUClast of IV midazolam (and its 1'-hydroxymidazolam metabolite) in the presence of ecopipam
Time Frame: Up to Day 18
Up to 38 blood samples will be collected at the indicated time points for pharmacokinetic
AUClast of IV midazolam (and its 1'-hydroxymidazolam metabolite) in the absence of ecopipam
Time Frame: Up to Day 18
Up to 38 blood samples will be collected at the indicated time points for pharmacokinetic
AUClast of oral midazolam (and its 1'-hydroxymidazolam metabolite) in the presence of ecopipam
Time Frame: Up to Day 18
Up to 38 blood samples will be collected at the indicated time points for pharmacokinetic
AUClast of oral midazolam (and its 1'-hydroxymidazolam metabolite) in the absence of ecopipam
Time Frame: Up to Day 18
Up to 38 blood samples will be collected at the indicated time points for pharmacokinetic
AUClast of dabigatran in the presence of ecopipam
Time Frame: Up to Day 18
Up to 38 blood samples will be collected at the indicated time points for pharmacokinetic
AUClast of dabigatran in the absence of ecopipam
Time Frame: Up to Day 18
Up to 38 blood samples will be collected at the indicated time points for pharmacokinetic
AUClast of pitavastatin (and its pitavastatin lactone metabolite) in the presence of ecopipam
Time Frame: Up to Day 18
Up to 38 blood samples will be collected at the indicated time points for pharmacokinetic
AUClast of pitavastatin (and its pitavastatin lactone metabolite) in the absence of ecopipam
Time Frame: Up to Day 18
Up to 38 blood samples will be collected at the indicated time points for pharmacokinetic
AUClast of rosuvastatin in the presence of ecopipam
Time Frame: Up to Day 18
Up to 38 blood samples will be collected at the indicated time points for pharmacokinetic
AUClast of rosuvastatin in the absence of ecopipam
Time Frame: Up to Day 18
Up to 38 blood samples will be collected at the indicated time points for pharmacokinetic
AUClast of atorvastatin (and its 4'-hydroxy atorvastatin metabolite) in the presence of ecopipam
Time Frame: Up to Day 18
Up to 38 blood samples will be collected at the indicated time points for pharmacokinetic
AUClast of atorvastatin (and its 4'-hydroxy atorvastatin metabolite) in the absence of ecopipam
Time Frame: Up to Day 18
Up to 38 blood samples will be collected at the indicated time points for pharmacokinetic
Cmax of pitavastatin (and its pitavastatin lactone metabolite) in the absence of ecopipam
Time Frame: Up to Day 18
Up to 38 blood samples will be collected at the indicated time points for pharmacokinetic analysis
Cmax of rosuvastatin in the absence of ecopipam
Time Frame: Up to Day 18
Up to 38 blood samples will be collected at the indicated time points for pharmacokinetic analysis
Cmax of atorvastatin (and its 4'-hydroxy atorvastatin metabolite) in the presence of ecopipam
Time Frame: Up to Day 18
Up to 38 blood samples will be collected at the indicated time points for pharmacokinetic analysis
AUCinf of dextromethorphan (and its dextrorphan metabolite) in the presence of ecopipam
Time Frame: Up to Day 18
Up to 38 blood samples will be collected at the indicated time points for pharmacokinetic analysis
AUCinf of dextromethorphan (and its dextrorphan metabolite) in the absence of ecopipam
Time Frame: Up to Day 18
Up to 38 blood samples will be collected at the indicated time points for pharmacokinetic analysis
AUCinf of IV midazolam (and its 1'-hydroxymidazolam metabolite) in the absence of ecopipam
Time Frame: Up to Day 18
Up to 38 blood samples will be collected at the indicated time points for pharmacokinetic analysis
Secondary Outcomes
- CL/F for dabigatran in the absence of ecopipam(Up to Day 18)
- CL/F for pitavastatin in the presence of ecopipam(Up to Day 18)
- CL/F for pitavastatin in the absence of ecopipam(Up to Day 18)
- CL/F for atorvastatin in the absence of ecopipam(Up to Day 18)
- CL/F for bupropion in the presence of ecopipam(Up to Day 18)
- V/F for dextromethorphan in the presence of ecopipam(Up to Day 18)
- CL/F for rosuvastatin in the presence of ecopipam(Up to Day 18)
- CL/F for bupropion in the absence of ecopipam(Up to Day 18)
- CL/F for caffeine in the absence of ecopipam(Up to Day 18)
- Safety and tolerability as demonstrated by MOAA/S(Up to Day 55)
- CL/F for rosuvastatin in the absence of ecopipam(Up to Day 18)
- CL/F for caffeine in the presence of ecopipam(Up to Day 18)
- V/F for IV midazolam in the presence of ecopipam(Up to Day 18)
- V/F for IV midazolam in the absence of ecopipam(Up to Day 18)
- CL/F for omeprazole in the presence of ecopipam(Up to Day 18)
- V/F for dextromethorphan in the absence of ecopipam(Up to Day 18)
- V/F for oral midazolam in the presence of ecopipam(Up to Day 18)
- Cmax of bupropion (and its 4-hydroxybupropion metabolite) in the presence of ecopipam(Up to Day 18)
- Cmax of bupropion (and its 4-hydroxybupropion metabolite) in the absence of ecopipam(Up to Day 18)
- CL/F for atorvastatin in the presence of ecopipam(Up to Day 18)
- CL/F for omeprazole in the absence of ecopipam(Up to Day 18)
- CL/F for dabigatran in the presence of ecopipam(Up to Day 18)
- Cmax of caffeine (and its metabolite paraxanthine) in the presence of ecopipam(Up to Day 18)
- Cmax of caffeine (and its metabolite paraxanthine) in the absence of ecopipam(Up to Day 18)
- Cmax omeprazole (and its 5'-hydroxy omeprazole metabolite) in the presence of ecopipam(Up to Day 18)
- Cmax omeprazole (and its 5'-hydroxy omeprazole metabolite) in the absence of ecopipam(Up to Day 18)
- AUCinf of bupropion (and its 4-hydroxybupropion metabolite) in the presence of ecopipam(Up to Day 18)
- AUCinf of bupropion (and its 4-hydroxybupropion metabolite) in the absence of ecopipam(Up to Day 18)
- AUCinf of caffeine (and its metabolite paraxanthine) in the presence of ecopipam(Up to Day 18)
- AUCinf of caffeine (and its metabolite paraxanthine) in the absence of ecopipam(Up to Day 18)
- AUCinf of omeprazole (and its 5'-hydroxy omeprazole metabolite) in the presence of ecopipam(Up to Day 18)
- AUCinf of omeprazole (and its 5'-hydroxy omeprazole metabolite) in the absence of ecopipam(Up to Day 18)
- AUClast of bupropion (and its 4-hydroxybupropion metabolite) in the presence of ecopipam(Up to Day 18)
- AUClast of bupropion (and its 4-hydroxybupropion metabolite) in the absence of ecopipam(Up to Day 18)
- AUClast of caffeine (and its metabolite paraxanthine) in the presence of ecopipam(Up to Day 18)
- AUClast of caffeine (and its metabolite paraxanthine) in the absence of ecopipam(Up to Day 18)
- AUClast of omeprazole (and its 5'-hydroxy omeprazole metabolite) in the presence of ecopipam(Up to Day 18)
- AUClast of omeprazole (and its 5'-hydroxy omeprazole metabolite) in the absence of ecopipam(Up to Day 18)
- CL/F for dextromethorphan in the presence of ecopipam(Up to Day 18)
- CL/F for dextromethorphan in the absence of ecopipam(Up to Day 18)
- CL/F for IV midazolam in the presence of ecopipam(Up to Day 18)
- CL/F for IV midazolam in the absence of ecopipam(Up to Day 18)
- CL/F for oral midazolam in the presence of ecopipam(Up to Day 18)
- CL/F for oral midazolam in the absence of ecopipam(Up to Day 18)
- V/F for oral midazolam in the absence of ecopipam(Up to Day 18)
- V/F for dabigatran in the presence of ecopipam(Up to Day 18)
- V/F for pitavastatin in the presence of ecopipam(Up to Day 18)
- V/F for pitavastatin in the absence of ecopipam(Up to Day 18)
- V/F for rosuvastatin in the presence of ecopipam(Up to Day 18)
- V/F for rosuvastatin in the absence of ecopipam(Up to Day 18)
- V/F for atorvastatin in the presence of ecopipam(Up to Day 18)
- V/F for atorvastatin in the absence of ecopipam(Up to Day 18)
- V/F for bupropion in the presence of ecopipam(Up to Day 18)
- V/F for bupropion in the absence of ecopipam(Up to Day 18)
- V/F for caffeine in the presence of ecopipam(Up to Day 18)
- V/F for caffeine in the absence of ecopipam(Up to Day 18)
- V/F for omeprazole in the presence of ecopipam(Up to Day 18)
- V/F for omeprazole in the absence of ecopipam(Up to Day 18)
- Total concentration of bilirubin in the presence of ecopipam(Up to Day 13)
- Total concentration of bilirubin in the absence of ecopipam(Up to Day 13)
- Unconjugated concentration of bilirubin in the presence of ecopipam(Up to Day 13)
- Unconjugated concentration of bilirubin in the absence of ecopipam(Up to Day 13)
- Safety and tolerability as demonstrated by C-SSRS(Up to Day 55)
- Safety and tolerability as demonstrated by concomitant medications(Up to Day 55)
- AEs with relatedness associated with dextromethorphan(Up to Day 55)
- AEs with relatedness associated with IV midazolam(Up to Day 55)
- AEs with relatedness associated with oral midazolam(Up to Day 55)
- AEs with relatedness associated with dabigatran(Up to Day 55)
- AEs with relatedness associated with pitavastatin(Up to Day 55)
- AEs with relatedness associated with rosuvastatin(Up to Day 55)
- AEs with relatedness associated with atorvastatin(Up to Day 55)
- AEs with relatedness associated with bupropion(Up to Day 55)
- V/F for dabigatran in the absence of ecopipam(Up to Day 18)
- Change from Day -1 to Day of Discharge in urine blood(Up to Day 25)
- AEs with relatedness associated with caffeine(Up to Day 55)
- AEs with relatedness associated with omeprazole(Up to Day 55)
- AEs with relatedness associated with ecopipam(Up to Day 55)
- Absolute values of white blood cell (WBC) count (K/Ul)(Up to Day 25)
- Absolute values of neutrophils, lymphocytes, monocytes, eosinophils, and basophils (10E3/uL)(Blood samples will be collected for the assessment of hematology parameters.)
- Absolute values of platelets (K/uL)(Up to Day 25)
- Absolute values of hematocrit (%)(Up to Day 25)
- Absolute values of hemoglobin (g/dL)(Up to Day 25)
- Absolute values of Red blood cell (RBC) count (M/uL)(Up to Day 25)
- Absolute values of blood sodium, magnesium, urea, phosphorus, potassium, and chloride (mg/dL)(Up to Day 25)
- Absolute values of creatinine, calcium, glucose, and direct and total bilirubin (mg/dL)(Up to Day 25)
- Absolute values of albumin and total protein (g/dL)(Up to Day 25)
- Absolute values of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), gamma glutamyl transferase (GGT), and creatinine phosphokinase (CPK) (U/L)(Up to Day 25)
- Absolute values of urine specific gravity(Up to Day 25)
- Absolute values of urine pH(Up to Day 25)
- Absolute values of urine glucose(Up to Day 25)
- Absolute values of urine protein(Up to Day 25)
- Absolute values of urine blood(Up to Day 25)
- Absolute values of urine ketones(Up to Day 25)
- Absolute values of urine bilirubin, urobilinogen, and nitrite(Up to Day 25)
- Absolute values of urine leukocytes by dipstick(Up to Day 25)
- Change from Day -1 to Day of Discharge in white blood cell (WBC) count (K/Ul)(Up to Day 25)
- Change from Day -1 to Day of Discharge in neutrophils, lymphocytes, monocytes, eosinophils, and basophils (10E3/uL)(Up to Day 25)
- Change from Day -1 to Day of Discharge in platelets (K/uL)(Up to Day 25)
- Change from Day -1 to Day of Discharge in hematocrit (%)(Up to Day 25)
- Change from Day -1 to Day of Discharge in hemoglobin (g/dL)(Up to Day 25)
- Change from Day -1 to Day of Discharge in Red blood cell (RBC) count (M/uL)(Up to Day 25)
- Change from Day -1 to Day of Discharge in blood sodium, magnesium, urea, phosphorus, potassium, and chloride (mg/dL)(Up to Day 25)
- Change from Day -1 to Day of Discharge in creatinine, calcium, glucose, and direct and total bilirubin (mg/dL)(Up to Day 25)
- Change from Day -1 to Day of Discharge in albumin and total protein (g/dL)(Up to Day 25)
- 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)(Up to Day 25)
- Change from Day -1 to Day of Discharge in urine specific gravity(Up to Day 25)
- Change from Day -1 to Day of Discharge in urine pH(Up to Day 25)
- Change from Day -1 to Day of Discharge in urine glucose(Up to Day 25)
- Change from Day -1 to Day of Discharge in urine protein(Up to Day 25)
- Change from Day -1 to Day of Discharge in urine ketones(Up to Day 25)
- Change from Day -1 to Day of Discharge in urine bilirubin, urobilinogen, and nitrite (Milligrams per deciliter)(Up to Day 25)
- Change from Day -1 to Day of Discharge in urine leukocytes by dipstick(Up to Day 25)
- Absolute values of electrocardiogram (ECG) parameters: PR, QRS, QT, and QT interval corrected for heart rate using Fridericia's formula (QTcF) (Milliseconds)(Up to Day 25)
- Change from pre-dose for the respective day in ECG parameters: PR, QRS, QT, and QTcF (Milliseconds)(Up to Day 25)
- Absolute values of oral temperature (degrees Celsius)(Up to Day 25)
- Change from pre-dose for the respective day in oral temperature (degrees Celsius)(Up to Day 25)
- Absolute values of heart rate (beats/minute)(Up to Day 25)
- Change from pre-dose for the respective day in heart rate (beats/minute)(Up to Day 25)
- Absolute values of respiratory rate (breaths/minute)(Up to Day 25)
- Change from pre-dose for the respective day in respiratory rate (breaths/minute)(Up to Day 25)
- Absolute values of systolic blood pressure (SBP) and diastolic blood pressure (DBP) (mmHG)(Up to Day 25)
- Change from pre-dose for the respective day in SBP and DBP (mmHG)(Up to Day 25)