Healthy Participants
Conditions
Keywords
E2082, male, single ascending dose, multiple ascending dose
Brief summary
This study will be conducted to evaluate the safety, tolerability, and pharmacokinetics (PK) of single ascending oral doses of E2082 in healthy Japanese adult and elderly male participants, and to evaluate the safety, tolerability, and PK of multiple ascending oral doses of E2082 in healthy Japanese and Caucasian adult male participants.
Interventions
DRUGE2082
Solution (0.2 mg) or tablet (0.5 mg and 5 mg).
DRUGPlacebo
Solution (0.2 mg) or tablet (0.5 mg and 5 mg) matched to E2082.
Sponsors
Eisai Co., Ltd.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
MALE
Age
20 Years to 85 Years
Healthy volunteers
Yes
Inclusion criteria
Participants must meet all of the following criteria to be included in this study: * Non-smoking, age ≥20 years and \<55 years old adult male (Cohorts 1 to 9 of Part A and all cohorts of Part B), or age ≥55 years and ≤85 years old elderly male (only Cohort 10 of Part A) at the time of informed consent. To be considered non-smokers, participants must have discontinued smoking for at least 4 weeks before dosing. * Body mass index ≥18 and \<30 kilograms per meters squared at Screening
Exclusion criteria
Participants who meet any of the following criteria will be excluded from this study: * Evidence of disease that may influence the outcome of the study within 4 weeks before dosing; example, 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 gastrointestinal surgery that may affect pharmacokinetic profiles of E2082, example, hepatectomy, nephrectomy, and digestive organ resection * Any clinically abnormal symptom or organ impairment found by medical history, physical examinations, vital signs, electrocardiogram finding, or laboratory test results that require medical treatment at Screening
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part B: Change from baseline in QT interval corrected for heart rate using the Fridericia formula (QTcF) | Baseline and Day 1 | — |
| Part B: Mean value of the average steady state concentration (Css,av) of E2082 for the MAD cohorts | Predose and 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, and 24 hours postdose of Day 10 | The average steady state concentration is calculated as AUC(0-τ)/τ. τ is the dosing interval. |
| Part B: Mean value of AUC(0-24h) after dosing on Day 1 for the MAD cohorts | Predose and 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, and 24 hours postdose of Day 1 | AUC(0-24h) represents the total drug exposure from zero time to 24 hours after dosing. |
| Part B: Mean value of AUC(0-τ) for the MAD cohorts | Predose and 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12 and 24 hours postdose of Day 10 | AUC(0-τ) is AUC over the dosing interval on multiple dosing. |
| Part B: Mean value of t½ following the last day of dosing for the MAD cohorts | Predose and 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 24, 48, 72, 96, 168, 240, and 336 hours postdose of Day 10 | t½ is the time required for the concentration or amount of drug in the body to be reduced to exactly one-half of a given concentration or amount. |
| Part B: Peak-trough fluctuation (PTF) for the MAD cohorts | Predose at Days 1, 2, 6, 10, 12, 13, and 14. 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, and 24 hours postdose of Day 1. 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 24, 48, 72, 96, 168, 240, and 336 hours postdose of Day 10 | PTF is peak to trough fluctuation at steady-state. |
| Part B: Accumulation ratio for AUC and Cmax (Rac) for the MAD cohorts | Predose at Days 1, 2, 6, 10, 12, 13, and 14. 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, and 24 hours postdose of Day 1. 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 24, 48, 72, 96, 168, 240, and 336 hours postdose of Day 10 | Rac (Cmax) is calculated as the ratio of drug concentrations observed during a dosing interval at steady-state divided by drug concentrations seen during the dosing interval after a single (first) dose. Rac (AUC)=steady state AUC(0-τ)/single dose AUC(0- τ), where τ is dosing interval. |
| Part B: Mean value of apparent total clearance at steady state (CLss/F) for the MAD cohorts on Day 10 | Predose and 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 24, 48, 72, 96, 168, 240, and 336 hours postdose of Day 10 | CLss/F is the apparent total clearance at steady state following extravascular (example, oral) administration. It is defined as the rate of drug elimination. |
| Part B: Mean value of Vz/F for the MAD cohorts on Day 10 | Predose and 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 24, 48, 72, 96, 168, 240, and 336 hours postdose of Day 10 | Vz/F is apparent volume of distribution at terminal phase on Day 10. |
| Part A: Mean value of the maximum observed concentration (Cmax) of E2082 under a fasted state for the single ascending dose (SAD) Cohorts 1-10 | Predose and 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 24 (Day 2), 48 (Day 3), 72 (Day 4), 96 (Day 5), and 168 (Day 8) hours postdose for all cohorts. Additionally, 240 (Day 11) and 336 (Day 15) hours postdose for Cohort 4 or later. | Cmax is the maximum observed concentration of E2082 in the plasma that is measured after a dose. |
| Part A: Mean value of Cmax of E2082 under a fed state for the SAD Cohort 5 | Predose and 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 24 (Day 2), 48 (Day 3), 72 (Day 4), 96 (Day 5), 168 (Day 8), 240 (Day 11), and 336 (Day 15) hours postdose | Cmax is the maximum observed concentration of E2082 in the plasma that is measured after a dose. |
| Part A: Mean value of the time at which the highest plasma concentration (Tmax) of E2082 occurs under a fasted state for the SAD Cohorts 1-10 | Predose and 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 24 (Day 2), 48 (Day 3), 72 (Day 4), 96 (Day 5), and 168 (Day 8) hours postdose for all cohorts. Additionally, 240 (Day 11) and 336 (Day 15) hours postdose for Cohort 4 or later. | Tmax is the time at which the highest concentration of E2082 occurs. |
| Part A: Mean value of Tmax of E2082 under fed state for the SAD Cohort 5 | Predose and 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 24 (Day 2), 48 (Day 3), 72 (Day 4), 96 (Day 5), 168 (Day 8), 240 (Day 11), and 336 (Day 15) hours postdose | Tmax is the time at which the highest concentration of E2082 occurs. |
| Part A: Mean value of the area under the concentration-time curve from zero time to 24 hours after dosing (AUC[0-24h]) under a fasted state for the SAD Cohorts 1-10 | Predose and 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, and 24 hours postdose | AUC(0-24h) represents the total drug exposure from zero time to 24 hours after dosing. |
| Part A: Mean value of AUC(0-24h) under a fed state for the SAD Cohort 5 | Predose and 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, and 24 hours postdose | AUC(0-24h) represents the total drug exposure from zero time to 24 hours after dosing. |
| Part A: Mean value of AUC from zero time to the time of the last quantifiable concentration (AUC[0-t]) under a fasted state for the SAD Cohorts 1-10 | Predose and 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 24 (Day 2), 48 (Day 3), 72 (Day 4), 96 (Day 5), and 168 (Day 8) hours postdose for all cohorts. Additionally, 240 (Day 11) and 336 (Day 15) hours postdose for Cohort 4 or later. | AUC(0-t) represents the total drug exposure from zero time to the time of the last quantifiable concentration. |
| Part A: Mean value of AUC(0-t) under a fed state for the SAD Cohort 5 | Predose and 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 24 (Day 2), 48 (Day 3), 72 (Day 4), 96 (Day 5), 168 (Day 8), 240 (Day 11), and 336 (Day 15) hours postdose | AUC(0-t) represents the total drug exposure from zero time to the time of the last quantifiable concentration. |
| Part A: Mean value of AUC from zero time to 72 hours after dosing (AUC[0-72h]) under a fasted state for the SAD Cohorts 1-10 | Predose and 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 24, 48, and 72 hours postdose | AUC(0-72h) represents the total drug exposure from zero time to 72 hours after dosing. |
| Part A: Mean value of AUC(0-72h) under a fed state for the SAD Cohort 5 | Predose and 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 24, 48, and 72 hours postdose | AUC(0-72h) represents the total drug exposure from zero time to 72 hours after dosing. |
| Part A: Mean value of AUC from zero time to 96 hours after dosing (AUC[0-96h]) under a fasted state for the SAD Cohorts 1-10 | Predose and 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 24, 48, 72, and 96 hours postdose | AUC(0-96h) represents the total drug exposure from zero time to 96 hours after dosing. |
| Part A: Mean value of AUC(0-96h) under a fed state for the SAD Cohort 5 | Predose and 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 24, 48, 72, and 96 hours postdose | AUC(0-96h) represents the total drug exposure from zero time to 96 hours after dosing. |
| Part A: Mean value of AUC from zero time extrapolated to infinite time (AUC[0-inf]) under a fasted state for the SAD Cohorts 1-10 | Predose and 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 24 (Day 2), 48 (Day 3), 72 (Day 4), 96 (Day 5), and 168 (Day 8) hours postdose for all cohorts. Additionally, 240 (Day 11) and 336 (Day 15) hours postdose for Cohort 4 or later. | AUC(0-inf) represents the total drug exposure from zero time extrapolated to infinite time. |
| Part A: Mean value of AUC(0-inf) under a fed state for the SAD Cohort 5 | Predose and 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 24 (Day 2), 48 (Day 3), 72 (Day 4), 96 (Day 5), 168 (Day 8), 240 (Day 11), and 336 (Day 15) hours postdose | AUC(0-inf) represents the total drug exposure from zero time extrapolated to infinite time. |
| Part A: Mean value of terminal elimination phase half-life (t½) of E2082 under a fasted state for the SAD Cohorts 1-10 | Predose and 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 24 (Day 2), 48 (Day 3), 72 (Day 4), 96 (Day 5), and 168 (Day 8) hours postdose for all cohorts. Additionally, 240 (Day 11) and 336 (Day 15) hours postdose for Cohort 4 or later. | t½ is the time required for the concentration or amount of drug in the body to be reduced to exactly one-half of a given concentration or amount. |
| Part A: Mean value of t½ of E2082 under a fed state for the SAD Cohort 5 | Predose and 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 24 (Day 2), 48 (Day 3), 72 (Day 4), 96 (Day 5), 168 (Day 8), 240 (Day 11), and 336 (Day 15) hours postdose | t½ is the time required for the concentration or amount of drug in the body to be reduced to exactly one-half of a given concentration or amount. |
| Part A: Mean value of apparent total clearance (CL/F) of E2082 under a fasted state for the SAD Cohorts 1-10 | Predose and 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 24 (Day 2), 48 (Day 3), 72 (Day 4), 96 (Day 5), and 168 (Day 8) hours postdose for all cohorts. Additionally, 240 (Day 11) and 336 (Day 15) hours postdose for Cohort 4 or later. | CL/F is the apparent total clearance following extravascular (example, oral) administration. |
| Part A: Mean value of CL/F of E2082 under a fasted state for the SAD Cohort 5 | Predose and 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 24 (Day 2), 48 (Day 3), 72 (Day 4), 96 (Day 5), 168 (Day 8), 240 (Day 11), and 336 (Day 15) hours postdose | CL/F is the apparent total clearance following extravascular (example, oral) administration. |
| Part A: Mean value of the apparent volume of distribution at terminal phase of E2082 on Day 1 (Vz/F) under a fasted state for the SAD Cohorts 1-10 | Predose and 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, and 12 hours postdose | The apparent volume of distribution gives information about the amount of drug distributed in body tissue rather than the plasma. |
| Part A: Mean value of Vz/F of E2082 on Day 1 under a fed state for the SAD Cohort 5 | Predose and 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, and 12 hours postdose | The apparent volume of distribution gives information about the amount of drug distributed in body tissue rather than the plasma. |
| Part B: Mean value of Cmax of E2082 for the multiple ascending dose (MAD) cohorts on Day 1 | Predose and 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, and 24 hours postdose of Day 1 | Cmax is the maximum observed concentration of E2082 in the plasma that is measured after a dose. |
| Part B: Mean value of Cmax of E2082 at steady state (Css,max) for the MAD cohorts on Day 10 | Predose and 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 24, 48, 72, 96, 168, 240, and 336 hours postdose of Day 10 | Cmax is the maximum observed concentration of E2082 in the plasma that is measured after a dose. |
| Part B: Mean value of the minimum observed concentration (Cmin) of E2082 for the MAD cohorts on Day 1 | Predose and 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, and 24 hours postdose of Day 1 | Cmin is the minimum observed concentration of E2082 in the plasma that is measured after a dose. |
| Part B: Mean value of Cmin of E2082 at steady state (Css,min) for the MAD cohorts | Predose and 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 24, 48, 72, 96, 168, 240, and 336 hours postdose of Day 10 | Css,min is the minimum observed concentration of E2082 in the plasma that is measured after a dose at steady state. |
| Part B: Mean value of Tmax of E2082 for the MAD cohorts on Day 1 | Predose and 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, and 24 hours postdose of Day 1 | Tmax is the time at which the highest concentration of E2082 occurs. |
| Part B: Mean value of Tmax of E2082 at steady state (Tss,max) for the MAD cohorts | Predose and 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 24, 48, 72, 96, 168, 240, and 336 hours postdose of Day 10 | Tss,max is the time at which the highest concentration of E2082 occurs at steady state. |
Secondary
| Measure | Time frame |
|---|---|
| Change from baseline in PR interval and QRS interval of the Electrocardiogram (ECG) | Baseline, Days 1 and 10 |
| Placebo-corrected change from baseline in HR | Baseline, Days 1 and 10 |
| Placebo-corrected change from baseline in QTcF, PR, QRS interval | Baseline, Days 1 and 10 |
| Number of participants with categorical outliers for HR, PR interval, QRS interval | Baseline up to Day 11 |
| Number of participants with categorical outliers defined as QTcF >450 msec, 480 msec and 500 msec at any timepoint and change-from-baseline QTcF (ΔQTcF) >30 msec (increased by 30 msec) and >60 msec | Baseline up to Day 11 |
| Number of participants with T wave morphology changes | Baseline up to Day 11 |
| Number of participants with U-wave presence | Baseline up to Day 11 |
| Change-from-baseline in heart rate (HR) | Baseline, Days 1 and 10 |
Countries
Japan
Outcome results
None listed