An Open-label, Single-Sequence, Drug-Drug Interaction Study to Evaluate the Effect of Diltiazem Extended Release on the Pharmacokinetics of E2027 in Healthy Subjects
Overview
- Phase
- Phase 1
- Intervention
- E2027
- Conditions
- Healthy Subjects
- Sponsor
- Eisai Co., Ltd.
- Enrollment
- 16
- Primary Endpoint
- Number of participants with any adverse event (AE) and any serious adverse event (SAE)
- Status
- Completed
- Last Updated
- 9 years ago
Overview
Brief Summary
This Phase 1, open-label, single-sequence, drug-drug Interaction study is conducted to evaluate the effect of diltiazem extended release (ER) (a moderate CYP3A inhibitor and P glycoprotein [Pgp] inhibitor) on the pharmacokinetics (PK) of a single oral dose of E2027 in healthy participants.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Non-smoking, male or female participants, ≥18 years old and ≤50 years old at the time of informed consent
- •Body mass index of 18 to 32 kilograms per meters squared (kg/m\^2) at Screening
Exclusion Criteria
- •Clinically significant illness that requires medical treatment within 8 weeks or a clinically significant infection that requires medical treatment within 4 weeks prior to the first dose
- •Females who are: (a) breastfeeding; or (b) pregnant at Screening or Baseline (documented by a negative beta human chorionic gonadotropin \[β-hCG\] (or human chorionic gonadotropin \[hCG\]) test with a sensitivity of at least 25 International Units per Liter (IU/L) or equivalent units of β-hCG \[or hCG\]). Note: A negative urine pregnancy test is required before the administration of the first dose.
- •Females of childbearing potential who:
- •Had unprotected sexual intercourse within 30 days before study entry and do not agree to use a highly effective method of contraception (e.g., total abstinence, an intrauterine device, a double barrier method \[such as condom plus diaphragm with spermicide\] or have a vasectomized partner with confirmed azoospermia) throughout the entire study period and for 28 days after study drug discontinuation. Note: Hormonal contraceptives are not allowed.
- •Are currently (for at least 30 days) abstinent, and do not agree to use a double barrier method (as described above) or refrain from sexual activity during the study period or for 28 days after study drug discontinuation NOTE: All females will be considered to be of childbearing potential unless they are postmenopausal (amenorrheic for at least 12 consecutive months, in the appropriate age group, and without other known or suspected cause) or have been sterilized surgically (i.e., bilateral tubal ligation, hysterectomy, or bilateral oophorectomy, all with surgery at least 1 month prior to first dose).
- •Males who have not had a successful vasectomy (confirmed azoospermia) or they and their female partners do not meet the criteria above (i.e., not of childbearing potential or practicing highly effective contraception throughout the study period or for 28 days after study drug discontinuation). No sperm donation is allowed during the study period or for 28 days after study drug discontinuation.
- •Evidence of disease that may influence the outcome of the study within 4 weeks prior to the first dose (e.g., psychiatric disorders and disorders of the gastrointestinal tract, liver, kidney, respiratory system, endocrine system, hematological system, neurological system, or cardiovascular system, or participants who have a congenital abnormality in metabolism)
- •Any history of abdominal surgery that may affect pharmacokinetic profiles of E2027 (e.g., hepatectomy, nephrectomy, digestive organ resection). Participants with a history cholecystectomy or appendectomy are not excluded.
- •Any other clinically abnormal symptom or organ impairment found by medical history, physical examinations, vital signs, electrocardiogram (ECG) finding (including a PR greater than 210 milliseconds (msec), a QRS greater than 110 msec), or laboratory test results that requires medical treatment at Screening or Baseline as determined by the Principal Investigator or designee
- •A prolonged QT/QTc interval (QTc greater than 450 msec) demonstrated on ECG at Screening or Baseline (based on average of triplicate ECGs). A history of risk factors for torsade de pointes (e.g., heart failure, hypokalemia, family history of long QT Syndrome) or the use of concomitant medications that prolonged the QT/QTc interval
Arms & Interventions
E2027 100 mg alone and in combination with diltiazem ER 300 mg
E2027 100 milligrams (mg) will be administered orally on Days 1 and 12. Diltiazem extended release (ER) 300 mg will be administered alone on Days 7 to 24; however, on the morning of Day 12 it will be coadministered with E2027 100 mg.
Intervention: E2027
E2027 100 mg alone and in combination with diltiazem ER 300 mg
E2027 100 milligrams (mg) will be administered orally on Days 1 and 12. Diltiazem extended release (ER) 300 mg will be administered alone on Days 7 to 24; however, on the morning of Day 12 it will be coadministered with E2027 100 mg.
Intervention: Diltiazem ER
Outcomes
Primary Outcomes
Number of participants with any adverse event (AE) and any serious adverse event (SAE)
Time Frame: up to Day 27
Mean area under the concentration x time curve from time zero to time 144 hours measurable concentration postdose (AUC[0-144]) for E2027 and metabolites at Day 1 and Day 12
Time Frame: Days 1 and 12: predose; 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 18 hours postdose
Mean area under the concentration x time curve from time zero to time infinity postdose (AUC[0-inf]) for E2027 and metabolites at Day 1 and Day 12
Time Frame: Days 1 and 12: predose; 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 18 hours postdose
Mean values for the indicated hematology and blood chemistry parameters at the indicated time points
Time Frame: Screening; Baseline; Day 6; Day 11; Follow-up/Early Termination (FU/ET) (Day 27); Unscheduled Visits
Mean urine values at the indicated time points
Time Frame: Screening; Baseline; Day 6; Day 11; FU/ET (Day 27); Unscheduled Visits
Mean values for the indicated vital signs at the indicated time points
Time Frame: Screening; Baseline; Days 1-6; Days 12-25; FU/ET (Day 27); Unscheduled Visits
Day 1: predose; 2, 4, 6, 8, and 12 hours postdose. Day 2: 24 hours postdose. Day 12: predose; 2, 4, 6, 8, and 12 hours postdose; Day 13: 24 hours postdose)
Mean values for the indicated electrocardiogram (ECG) parameters at the indicated time points
Time Frame: Screening; Baseline; Days 1-6; Days 12-25; FU/ET (Day 27); Unscheduled Visits
Day 1: predose; 2, 4, 6, 8, and 12 hours postdose. Day 2: 24 hours postdose. Day 12: predose; 2, 4, 6, 8, and 12 hours postdose. Day 13: 24 hours postdose
Mean values for the indicted physical examination parameters at the indicated time points
Time Frame: Screening; Baseline; Day 11; Day 25; FU/ET (Day 27); Unscheduled Visits
Mean maximum drug concentration (Cmax) for E2027 and metabolites at Day 1 and Day 12
Time Frame: Days 1 and 12: predose; 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 18 hours postdose
Secondary Outcomes
- Mean area under the concentration x time curve from time zero to time 72 hours measurable concentration postdose (AUC[0-72]) for E2027 and metabolites at Day 1 and Day 12(Days 1 and 12: predose; 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 18 hours postdose)
- Mean time to reach maximum (peak) concentration (tmax) for E2027 and metabolites at Day 1 and Day 12(Days 1 and 12: predose; 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 18 hours postdose)
- Mean apparent total body clearance after oral administration (CL/F) for E2027 at Day 1 and Day 12(Days 1 and 12: predose; 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 18 hours postdose)
- Mean terminal elimination half-life (t1/2) for E2027 and metabolites at Day 1 and Day 12(Days 1 and 12: predose; 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 18 hours postdose)
- Mean apparent volume of distribution in the terminal phase (Vz/F) for E2027 at Day 1 and Day 12(Days 1 and 12: predose; 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 18 hours postdose)