An Open-label, Healthy Subject, Two-part Study to Assess the Effect of Verapamil on Systemic Exposure of EP395 (Part A), and to Assess the Effect of EP395 on Systemic Exposure of Midazolam and Digoxin (Part B)
Overview
- Phase
- Phase 1
- Status
- Completed
- Sponsor
- EpiEndo Pharmaceuticals
- Enrollment
- 37
- Locations
- 2
- Primary Endpoint
- Part A: PK parameters of EP395 - Vz/F
Overview
Brief Summary
The aim of this trial is to assess the potential key drug-drug interactions with EP395 in the clinical setting.
Detailed Description
This is an open-label, healthy subject, two-part study to assess the effect of verapamil on systemic exposure of EP395 (Part A), and to assess the effect of EP395 on systemic exposure of midazolam and digoxin (Part B).
The overall aim of this trial is to assess the potential key drug-drug interactions (DDIs) with EP395 in the clinical setting. The trial will be in two parts:
Part A will investigate EP395 as a 'victim' of DDIs. The impact of CYP3A4 and P-glycoprotein (Pgp) inhibition on the pharmacokinetics (PK) of EP395 will be assessed. Verapamil has been selected as a moderate inhibitor of CYP3A4 and an inhibitor of Pgp.
Part B will investigate EP395 as a 'perpetrator' of DDIs. The impact of EP395 on the PK of a CYP3A4 substrate and a Pgp substrate will be assessed. Midazolam has been selected as the CYP3A4 substrate and digoxin as the Pgp substrate.
The trial population is healthy adults.
Study Design
- Study Type
- Interventional
- Allocation
- Non Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to 55 Years (Adult)
- Sex
- All
- Accepts Healthy Volunteers
- Yes
Inclusion Criteria
- •Willing and able to understand the information on the nature, the scope, and the relevance of the trial, and to provide voluntary, written informed consent to participate in the trial before any trial-related procedures.
- •Healthy male or female participant aged 18 to 55 years, inclusive.
- •Body mass index ≥ 19.0 and ≤ 33.0 kg/m2 at the time of the screening visit.
- •Medically healthy participant without abnormal clinically significant medical history, physical findings, vital signs, ECG and laboratory values at the time of the screening visit, as judged by the Investigator.
- •Non-smoker, or former smoker with \<10 pack years who stopped smoking (including e-cigarettes) at least 6 months before the screening visit.
- •Women of childbearing potential (WOCBP) must:
- •have a negative pregnancy test (blood) at the screening visit and (urine) Day
- •agree to use, and be able to comply with, highly effective measures of contraceptive control (failure rate less than 1% per year when used consistently and correctly) without interruption, during trial participation and until 90 days after the last IMP intake.
- •agree to abstain from breast feeding during the trial participation and for 90 days after the last IP intake.
- •Women defined as of non-childbearing potential are postmenopausal (no menses for at least 1 year without alternative medical cause \[follicle stimulating hormone, FSH, measurement in serum may be done as additional confirmation at Investigator's discretion\]) or surgically sterile women (tubal ligation, hysterectomy, or bilateral oophorectomy).
Exclusion Criteria
- •Participants must not enter the trial if any of the following exclusion criteria are fulfilled:
- •History of any clinically significant disease or disorder which, in the opinion of the Investigator, may either put the participant at risk because of participation in the trial, or influence the results, or the participant's ability to participate in the trial.
- •Any clinically significant illness, medical/surgical procedure or trauma within 4 weeks of the (first) administration of IMP.
- •Presence or history of lung disease, e.g., asthma, chronic obstructive pulmonary disease.
- •Presence or history of significant gastrointestinal medical condition that could lead to abnormal absorption.
- •History of or active tuberculosis at the time of the screening visit based on participant anamnesis. Participants who have been living together with another person with active tuberculosis at any time over the past 10 years will also be excluded.
- •Clinically significant abnormality on 12-lead ECG at the screening visit or Day 1 pre-dose, including prolonged QTcF (\>450 msec men or \>470 msec women) or PR interval \>210 msec.
- •Abnormal renal function at the time of the screening visit:
- •serum creatinine \>upper limit of normal (ULN); and/or
- •estimated glomerular filtration rate \<60 mL/min according to the revised Lund-Malmö GFR estimating equation.
Arms & Interventions
Part A - EP395 as a 'victim' of DDIs
Part A will investigate EP395 as a 'victim' of DDIs. The impact of CYP3A4 and P-glycoprotein (Pgp) inhibition on the pharmacokinetics (PK) of EP395 will be assessed. Verapamil has been selected as a moderate inhibitor of CYP3A4 and an inhibitor of Pgp.
Intervention: Verapamil (Part A) (Drug)
Part B - EP395 as a 'perpetrator' of DDIs
Part B will investigate EP395 as a 'perpetrator' of DDIs. The impact of EP395 on the PK of a CYP3A4 substrate and a Pgp substrate will be assessed. Midazolam has been selected as the CYP3A4 substrate and digoxin as the Pgp substrate.
Intervention: EP395 (Part A and B) (Drug)
Part A - EP395 as a 'victim' of DDIs
Part A will investigate EP395 as a 'victim' of DDIs. The impact of CYP3A4 and P-glycoprotein (Pgp) inhibition on the pharmacokinetics (PK) of EP395 will be assessed. Verapamil has been selected as a moderate inhibitor of CYP3A4 and an inhibitor of Pgp.
Intervention: EP395 (Part A and B) (Drug)
Part B - EP395 as a 'perpetrator' of DDIs
Part B will investigate EP395 as a 'perpetrator' of DDIs. The impact of EP395 on the PK of a CYP3A4 substrate and a Pgp substrate will be assessed. Midazolam has been selected as the CYP3A4 substrate and digoxin as the Pgp substrate.
Intervention: Midazolam (Part B) (Drug)
Part B - EP395 as a 'perpetrator' of DDIs
Part B will investigate EP395 as a 'perpetrator' of DDIs. The impact of EP395 on the PK of a CYP3A4 substrate and a Pgp substrate will be assessed. Midazolam has been selected as the CYP3A4 substrate and digoxin as the Pgp substrate.
Intervention: Digoxin (Part B) (Drug)
Outcomes
Primary Outcomes
Part A: PK parameters of EP395 - Vz/F
Time Frame: Days 1 to 6 and Day 14 to 19
Volume of distribution following extravascular administration of EP395.
Part A: PK parameters of EP395 - AUC0-24
Time Frame: Days 1 to 6 and Day 14 to 19
Area under the plasma concentration vs. time curve from timepoint 0 to 24 hours of EP395.
Part A: PK parameters of EP395 - CL/F
Time Frame: Days 1 to 6 and Day 14 to 19
Apparent total body clearance following extravascular administration of EP395.
Part B: PK parameters of midazolam and digoxin - AUC0-inf
Time Frame: Days 1 to 3/6 and Day 24 to 29
Area under the plasma concentration vs. time curve from timepoint 0 to infinity of midazolam and digoxin.
Part B: PK parameters of midazolam and digoxin - T1/2
Time Frame: Days 1 to 3/6 and Day 24 to 29
Terminal elimination half-life of midazolam and digoxin.
Part A: PK parameters of EP395 - T1/2
Time Frame: Days 1 to 6 and Day 14 to 19
Terminal elimination half-life of EP395.
Part B: PK parameters of midazolam and digoxin - AUC0-24
Time Frame: Days 1 to 3/6 and Day 24 to 29
Area under the plasma concentration vs. time curve from timepoint 0 to 24 hours of midazolam and digoxin.
Part B: PK parameters of midazolam and digoxin - AUC%extrap
Time Frame: Days 1 to 3/6 and Day 24 to 29
Percent of AUCinf derived from extrapolation of the plasma concentration vs. time curve of midazolam and digoxin.
Part B: PK parameters of midazolam and digoxin - Tmax
Time Frame: Days 1 to 3/6 and Day 24 to 29
Time to occurrence of Cmax of midazolam and digoxin.
Part A: PK parameters of EP395 - AUC0-inf
Time Frame: Days 1 to 6 and Day 14 to 19
Area under the plasma concentration vs. time curve from timepoint 0 to infinity of EP395.
Part B: PK parameters of midazolam and digoxin - Cmax
Time Frame: Days 1 to 3/6 and Day 24 to 29
Maximum observed plasma concentration of midazolam and digoxin.
Part A: PK parameters of EP395 - AUC%extrap
Time Frame: Days 1 to 6 and Day 14 to 19
Percent of AUCinf derived from extrapolation of the plasma concentration vs. time curve of EP395.
Part A: PK parameters of EP395 - Cmax
Time Frame: Days 1 to 6 and Day 14 to 19
Maximum observed plasma concentration of EP395.
Part A: PK parameters of EP395 - Tmax
Time Frame: Days 1 to 6 and Day 14 to 19
Time to occurrence of Cmax of EP395.
Secondary Outcomes
- Part A: Absolute change from baseline in 12-lead Electrocardiogram (ECG) parameters (heart rate)(Screening (Day -28 to Day -1), Day 1, Day 10-19)
- Part A: Assessment of adverse event occurrence(From screening to Day 30.)
- Part A: Absolute change from baseline in vital signs (Systolic and diastolic blood pressure)(Screening (Day -28 to Day -1), Day 1, Day 10-19)
- Part A: Absolute change from baseline in safety laboratory analytes (haematology).(Screening (Day -28 to Day -1), Day -1, Day 10, Day 14, Day 19)
- Part B: Assessment of adverse event occurrence(From screening to Day 30.)
- Part B: Absolute change from baseline in safety laboratory analytes (haematology).(Screening (Day -28 to Day -1), Day -1, Day 9, Day 16, Day 23, D28)
- Part A: Absolute change from baseline in 12-lead Electrocardiogram (ECG) parameters (PQ/PR interval)(Screening (Day -28 to Day -1), Day 1, Day 10-19)
- Part A: Absolute change from baseline in 12-lead Electrocardiogram (ECG) parameters (QRS interval)(Screening (Day -28 to Day -1), Day 1, Day 10-19)
- Part A: Absolute change from baseline in 12-lead Electrocardiogram (ECG) parameters (QT interval)(Screening (Day -28 to Day -1), Day 1, Day 10-19)
- Part A: Absolute change from baseline in 12-lead Electrocardiogram (ECG) parameters (QTcF interval)(Screening (Day -28 to Day -1), Day 1, Day 10-19)
- Part A: Absolute change from baseline in safety laboratory analytes (clinical chemistry).(Screening (Day -28 to Day -1), Day -1, Day 10, Day 14, Day 19)
- Part A: Absolute change from baseline in safety laboratory analytes (coagulation).(Screening (Day -28 to Day -1), Day -1, Day 10, Day 14, Day 19)
- Part B: Absolute change from baseline in 12-lead Electrocardiogram (ECG) parameters(Screening (Day -28 to Day -1), Day 1, Day 9, Day 16, Day 24, Day 28)
- Part B: Absolute change from baseline in vital signs (Pulse)(Screening (Day -28 to Day -1), Day 1, Day 9, Day 16, Day 24, Day 28)
- Part B: Absolute change from baseline in 12-lead Electrocardiogram (ECG) parameters (QT interval).(Screening (Day -28 to Day -1), Day 1, Day 9, Day 16, Day 24, Day 28)
- Part B: Absolute change from baseline in safety laboratory analytes (coagulation).(Screening (Day -28 to Day -1), Day -1, Day 9, Day 16, Day 23, D28)
- Part A: Absolute change from baseline in vital signs (Pulse)(Screening (Day -28 to Day -1), Day 1, Day 10-19)
- Part B: Absolute change from baseline in 12-lead Electrocardiogram (ECG) parameters (PQ/PRinterval).(Screening (Day -28 to Day -1), Day 1, Day 9, Day 16, Day 24, Day 28)
- Part B: Absolute change from baseline in safety laboratory analytes (clinical chemistry).(Screening (Day -28 to Day -1), Day -1, Day 9, Day 16, Day 23, D28)
- Part B: Absolute change from baseline in vital signs (Systolic and diastolic blood pressure)(Screening (Day -28 to Day -1), Day 1, Day 9, Day 16, Day 24, Day 28)
- Part B: Absolute change from baseline in 12-lead Electrocardiogram (ECG) parameters (heart rate).(Screening (Day -28 to Day -1), Day 1, Day 9, Day 16, Day 24, Day 28)
- Part B: Absolute change from baseline in 12-lead Electrocardiogram (ECG) parameters (QRS interval).(Screening (Day -28 to Day -1), Day 1, Day 9, Day 16, Day 24, Day 28)
- Part B: PK parameters of EP395 and its major metabolites (Cmax)(Days 1 to 3/6 and Day 24 to 29)
- Part B: Absolute change from baseline in 12-lead Electrocardiogram (ECG) parameters (QTcF interval).(Screening (Day -28 to Day -1), Day 1, Day 9, Day 16, Day 24, Day 28)
- Part B: PK parameters of EP395 and its major metabolites (AUC0-24)(Days 1 to 3/6 and Day 24 to 29)