A Phase 1, First-in-Human Study to Evaluate the Safety, Tolerability, and Pharmacokinetic Profiles of Single Ascending and Multiple Oral Doses of MB-110 and to Evaluate the Antiviral Activity in Hepatitis C Virus Infected Patients
Trial Snapshot
- Phase
- Phase 1
- Sponsor
- Microbio Co Ltd
- Enrollment
- 40
- Locations
- 1
- Primary Endpoint
- Changes in 12-lead ECG from baseline in cohort 5
Study Overview
Brief Summary
A Phase 1, First-in-Human, Randomized, Placebo-Controlled, Double-Blind Study to Evaluate the Safety, Tolerability, and Pharmacokinetic Profiles of Single Ascending and Multiple Oral Doses of MB-110 in Healthy Volunteers and to Evaluate the Antiviral Activity of MB-110 in Hepatitis C Virus Infected Subjects
Detailed Description
The present study is divided into 2 parts. Part A is a randomized, double blind, placebo controlled, sequential ascending single and multiple oral doses design to evaluate the safety, tolerability, PK, and food effect of MB-110 in healthy volunteers.Part A will recruit 2 groups (Groups 1 and 2) of 8 healthy volunteers in each group. Within each group, 8 subjects will be randomized 6:2 to receive MB-110 versus placebo.Subjects in Group 1 will receive either 50 mg of MB-110 or placebo under fasted conditions during the first visit (Cohort 1); and either 50 mg of MB-110 or placebo under fed conditions during the second visit (Cohort 3) where food effect will be evaluated. Subjects in Group 2 will receive either 100 mg of MB-110 or placebo under fasted condition during the first visit (Cohort 2); or 200 mg of MB-110 or placebo under fasted condition during the second visit (Cohort 4). In Cohort 5, 8 subjects will be selected from Group 1, Group 2, or new recruitment if the washout time is insufficient from the previous cohort. Subjects in Cohort 5 will be randomized 6:2 to receive MB-110 at dose of 200 mg or placebo once daily for 5 consecutive days.
Part B is a randomized, double-blind, placebo-controlled, multiple ascending oral dose design to evaluate the safety, tolerability, PK, and antiviral activity of MB-110 in subjects infected with Hepatitis C virus genotype 1b, 2a, and 3a.Part B will recruit 3 cohorts (Cohorts 6, 7, and 8) of treatment-naïve HCV infected subjects in each cohort. In Cohort 6, 12 subjects infected with Hepatitis C virus genotype 1b will be randomized 5:5:2 to receive two dose levels of MB-110 or placebo once daily for 3 consecutive days. In Cohort 7, 6 subjects infected with Hepatitis C virus genotype 2a will be randomized 5:1 to receive MB-110 or placebo once daily for 3 consecutive days. In Cohort 8, 6 subjects infected with Hepatitis C virus genotype 3a will be randomized 5:1 to receive MB-110 or placebo once daily for 3 consecutive days.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- Double (Participant, Investigator)
Eligibility Criteria
- Ages
- 20 Years to 65 Years (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- Yes
Inclusion Criteria
- Not provided
Exclusion Criteria
- Not provided
Arms & Interventions
MB-110
oral hard-gel capsule formulation. One dose strength, 25 mg of MB-110, will be filled into the #00 hard-gel capsule.
Intervention: MB-110 (Drug)
Placebo
in the same #00 hard-gel capsules.
Intervention: Placebo (Drug)
Outcomes
Primary Outcomes
Changes in 12-lead ECG from baseline in cohort 5
Time Frame: at screening visit, day-1, post-1st, -2nd, -3rd, -4th, -5th dose (4 hr±15 min and 6 hr±15 min), discharge day (Day 9), and Day 12 (7 days plus or minus 1 day after dosing for 5 consecutive days)
Changes in 12-lead ECG from baseline in cohort 6-8
Time Frame: at screening visit, day-1, post-1st, -2nd, -3rd dose (4 hr±15 min and 6 hr±15 min), discharge day (Day 7), and Day 13 (10 days plus or minus 1 day after dosing for 3 consecutive days)
Change in plasma viral RNA from baseline in cohort 6-8
Time Frame: Up to 17 days
Blood for HCV RNA level determination will be collected at screening visit, day-1, Day 1 ( pre-1st dose (-2 to 0 hr), post-1st dose (8 hr±15 min, 16 hr±15 min, 24 hr±15 min before the 2nd dose)), Day 2 (post-2nd dose (12 hr±15 min and 24 hr±15 min)), Day 3 (post-3rd dose (12 hr±15 min, 24 hr±15 min, 48 hr±15 min, 72 hr±15 min, 96 hr±15 min)), Day 13, and Day 17
Incidence of adverse events in cohort 5
Time Frame: Up to 19 days (14 days plus or minus 1 day after dosing for 5 consecutive days)
Area under the plasma concentration time curve from 0 to the last measurable concentration (AUC0-t) in cohort 1-4
Time Frame: pre-dose (-2 to 0 hr) and post-dose (1 hr±3 min, 2 hr±5 min, 3 hr±10 min, 4 hr±10 min, 6 hr±15 min, 8 hr±15 min, 12 hr±15 min, 16 hr±15 min, 24 hr±15 min, 36 hr±15 min, 48 hr±15 min, 72 hr±15 min, 96 hr±15 min)
Area under the plasma concentration time curve from 0 to infinity (AUC0-inf) in cohort 1-4
Time Frame: pre-dose (-2 to 0 hr) and post-dose (1 hr±3 min, 2 hr±5 min, 3 hr±10 min, 4 hr±10 min, 6 hr±15 min, 8 hr±15 min, 12 hr±15 min, 16 hr±15 min, 24 hr±15 min, 36 hr±15 min, 48 hr±15 min, 72 hr±15 min, 96 hr±15 min)
Maximum plasma concentration (Cmax) in cohort 1-4
Time Frame: pre-dose (-2 to 0 hr) and post-dose (1 hr±3 min, 2 hr±5 min, 3 hr±10 min, 4 hr±10 min, 6 hr±15 min, 8 hr±15 min, 12 hr±15 min, 16 hr±15 min, 24 hr±15 min, 36 hr±15 min, 48 hr±15 min, 72 hr±15 min, 96 hr±15 min)
Trough plasma concentration (Cmin) in cohort 1-4
Time Frame: pre-dose (-2 to 0 hr) and post-dose (1 hr±3 min, 2 hr±5 min, 3 hr±10 min, 4 hr±10 min, 6 hr±15 min, 8 hr±15 min, 12 hr±15 min, 16 hr±15 min, 24 hr±15 min, 36 hr±15 min, 48 hr±15 min, 72 hr±15 min, 96 hr±15 min)
Time at which maximum plasma concentration (Tmax) is observed in cohort 1-4
Time Frame: pre-dose (-2 to 0 hr) and post-dose (1 hr±3 min, 2 hr±5 min, 3 hr±10 min, 4 hr±10 min, 6 hr±15 min, 8 hr±15 min, 12 hr±15 min, 16 hr±15 min, 24 hr±15 min, 36 hr±15 min, 48 hr±15 min, 72 hr±15 min, 96 hr±15 min)
Terminal elimination half-life (t1/2) in cohort 1-4
Time Frame: pre-dose (-2 to 0 hr) and post-dose (1 hr±3 min, 2 hr±5 min, 3 hr±10 min, 4 hr±10 min, 6 hr±15 min, 8 hr±15 min, 12 hr±15 min, 16 hr±15 min, 24 hr±15 min, 36 hr±15 min, 48 hr±15 min, 72 hr±15 min, 96 hr±15 min)
Terminal elimination rate constant (λz) in cohort 1-4
Time Frame: pre-dose (-2 to 0 hr) and post-dose (1 hr±3 min, 2 hr±5 min, 3 hr±10 min, 4 hr±10 min, 6 hr±15 min, 8 hr±15 min, 12 hr±15 min, 16 hr±15 min, 24 hr±15 min, 36 hr±15 min, 48 hr±15 min, 72 hr±15 min, 96 hr±15 min)
Urine PK parameters: the amount of study drug excreted into urine and urine recovery rate (Ae%) in cohort 1-4
Time Frame: -2-0 hr, 0-6 hr, 6-12 hr, 12-24 hr, 24-36 hr, 36-48 hr, 48-72 hr, 72-96 hr post-dose
Area under the plasma concentration time curve from 0 to the last measurable concentration (AUC0-t) in cohort 5
Time Frame: Up to 8 days
Day 1: pre-1st dose (-2 to 0 hr), post-1st dose (1 hr±3 min, 2 hr±5 min, 3 hr±10 min, 4 hr±10 min, 6 hr±15 min, 8 hr±15 min, 12 hr±15 min, 16 hr±15 min, 24 hr±15 min before the 2nd dose) Day 3 and Day 4: pre-3rd, -4th dose (-2 to 0 hr) Day 5: pre-5th dose (-2 to 0 hr), post-5th dose (1 hr±3 min, 2 hr±5 min, 3 hr±10 min, 4 hr±10 min, 6 hr±15 min, 8 hr±15 min, 12 hr±15 min, 16 hr±15 min, 24 hr±15 min, 36 hr±15 min, 48 hr±15 min, 72 hr±15 min, 96 hr±15 min)
Incidence of adverse events in cohort 6-8
Time Frame: Up to 17 days (14 days plus or minus 1 day after dosing for 3 consecutive days)
Changes in safety laboratory values (biochemistry, hematology, coagulation, and urinalysis) from baseline in cohort 1-4
Time Frame: at screening visit, day-1, and post-dose (12 hr±30 min, 48 hr±30 min, and 96 hr±30 min), and Day 8 (plus or minus 1 day)
Changes in safety laboratory values (biochemistry, hematology, coagulation, and urinalysis) from baseline in cohort 5
Time Frame: at screening visit, day-1, post-1st, -3rd, and -5th dose (12 hr±30 min), Day 7, discharge day (Day 9), and Day 12 (7 days plus or minus 1 day after dosing for 5 consecutive days)
Changes in safety laboratory values (biochemistry, hematology, coagulation, and urinalysis) from baseline in cohort 6-8
Time Frame: at screening visit, day-1, 12 hr±30 min post-1st, 12 hr±30 min post-3rd, Day 5, discharge day (Day 7), and Day 13 (10 days plus or minus 1 day after dosing for 3 consecutive days)
Changes in 12-lead ECG from baseline in cohort 1-4
Time Frame: at screening visit, day-1, pre-dose (-2 to 0 hr), and post-dose (2 hr, 4 hr, 6 hr, 8 hr, 12 hr, 16 hr, 24 hr, 48 hr, 72 hr, and 96 hr), and Day 8 (plus or minus 1 day)
Incidence of adverse events in cohort 1-4
Time Frame: Up to 8 days (plus or minus 1 day)
Changes in vital signs from baseline in cohort 1-4
Time Frame: at screening visit, day-1, pre-dose (-2 to 0 hr), and post-dose (2 hr, 4 hr, 6 hr, 8 hr, 12 hr, 16 hr, 24 hr, 48 hr, 72 hr, and 96 hr) and Day 8 (plus or minus 1 day)
Changes in vital signs from baseline in cohort 5
Time Frame: at screening visit, day-1, post-1st, -2nd, -3rd, -4th, -5th dose (4 hr±15 min and 6 hr±15 min), discharge day (Day 9), Day 12, and Day 19 (14 days plus or minus 1 day after dosing for 5 consecutive days)
vital signs will be performed
Changes in vital signs from baseline in cohort 6-8
Time Frame: at screening visit, day-1, post-1st, -2nd, -3rd dose (4 hr±15 min and 6 hr±15 min), discharge day (Day 7), Day 13, and Day 17 (14 days plus or minus 1 day after dosing for 3 consecutive days)
Changes in physical examination from baseline in cohort 1-4
Time Frame: at screening visit, day-1, discharge day (Day 5), and Day 8 (plus or minus 1 day)
Changes in physical examination from baseline in cohort 5
Time Frame: at screening visit, day-1, discharge day (Day 9), Day 12, and Day 19 (14 days plus or minus 1 day after dosing for 5 consecutive days)
Changes in physical examination from baseline in cohort 6-8
Time Frame: at screening visit, day-1, discharge day (Day 7), Day 13, and Day 17 (14 days plus or minus 1 day after dosing for 3 consecutive days)
Area under the plasma concentration time curve from 0 to infinity (AUC0-inf) in cohort 5
Time Frame: Up to 8 days
Day 1: pre-1st dose (-2 to 0 hr), post-1st dose (1 hr±3 min, 2 hr±5 min, 3 hr±10 min, 4 hr±10 min, 6 hr±15 min, 8 hr±15 min, 12 hr±15 min, 16 hr±15 min, 24 hr±15 min before the 2nd dose) Day 3 and Day 4: pre-3rd, -4th dose (-2 to 0 hr) Day 5: pre-5th dose (-2 to 0 hr), post-5th dose (1 hr±3 min, 2 hr±5 min, 3 hr±10 min, 4 hr±10 min, 6 hr±15 min, 8 hr±15 min, 12 hr±15 min, 16 hr±15 min, 24 hr±15 min, 36 hr±15 min, 48 hr±15 min, 72 hr±15 min, 96 hr±15 min)
Maximum plasma concentration (Cmax) in cohort 5
Time Frame: Up to 8 days
Day 1: pre-1st dose (-2 to 0 hr), post-1st dose (1 hr±3 min, 2 hr±5 min, 3 hr±10 min, 4 hr±10 min, 6 hr±15 min, 8 hr±15 min, 12 hr±15 min, 16 hr±15 min, 24 hr±15 min before the 2nd dose) Day 3 and Day 4: pre-3rd, -4th dose (-2 to 0 hr) Day 5: pre-5th dose (-2 to 0 hr), post-5th dose (1 hr±3 min, 2 hr±5 min, 3 hr±10 min, 4 hr±10 min, 6 hr±15 min, 8 hr±15 min, 12 hr±15 min, 16 hr±15 min, 24 hr±15 min, 36 hr±15 min, 48 hr±15 min, 72 hr±15 min, 96 hr±15 min)
Trough plasma concentration (Cmin) in cohort 5
Time Frame: Up to 8 days
Day 1: pre-1st dose (-2 to 0 hr), post-1st dose (1 hr±3 min, 2 hr±5 min, 3 hr±10 min, 4 hr±10 min, 6 hr±15 min, 8 hr±15 min, 12 hr±15 min, 16 hr±15 min, 24 hr±15 min before the 2nd dose) Day 3 and Day 4: pre-3rd, -4th dose (-2 to 0 hr) Day 5: pre-5th dose (-2 to 0 hr), post-5th dose (1 hr±3 min, 2 hr±5 min, 3 hr±10 min, 4 hr±10 min, 6 hr±15 min, 8 hr±15 min, 12 hr±15 min, 16 hr±15 min, 24 hr±15 min, 36 hr±15 min, 48 hr±15 min, 72 hr±15 min, 96 hr±15 min)
Time at which maximum plasma concentration (Tmax) is observed in cohort 5
Time Frame: Up to 8 days
Day 1: pre-1st dose (-2 to 0 hr), post-1st dose (1 hr±3 min, 2 hr±5 min, 3 hr±10 min, 4 hr±10 min, 6 hr±15 min, 8 hr±15 min, 12 hr±15 min, 16 hr±15 min, 24 hr±15 min before the 2nd dose) Day 3 and Day 4: pre-3rd, -4th dose (-2 to 0 hr) Day 5: pre-5th dose (-2 to 0 hr), post-5th dose (1 hr±3 min, 2 hr±5 min, 3 hr±10 min, 4 hr±10 min, 6 hr±15 min, 8 hr±15 min, 12 hr±15 min, 16 hr±15 min, 24 hr±15 min, 36 hr±15 min, 48 hr±15 min, 72 hr±15 min, 96 hr±15 min)
Terminal elimination half-life (t1/2) in cohort 5
Time Frame: Up to 8 days
Day 1: pre-1st dose (-2 to 0 hr), post-1st dose (1 hr±3 min, 2 hr±5 min, 3 hr±10 min, 4 hr±10 min, 6 hr±15 min, 8 hr±15 min, 12 hr±15 min, 16 hr±15 min, 24 hr±15 min before the 2nd dose) Day 3 and Day 4: pre-3rd, -4th dose (-2 to 0 hr) Day 5: pre-5th dose (-2 to 0 hr), post-5th dose (1 hr±3 min, 2 hr±5 min, 3 hr±10 min, 4 hr±10 min, 6 hr±15 min, 8 hr±15 min, 12 hr±15 min, 16 hr±15 min, 24 hr±15 min, 36 hr±15 min, 48 hr±15 min, 72 hr±15 min, 96 hr±15 min)
Terminal elimination rate constant (λz) in cohort 5
Time Frame: Up to 8 days
Day 1: pre-1st dose (-2 to 0 hr), post-1st dose (1 hr±3 min, 2 hr±5 min, 3 hr±10 min, 4 hr±10 min, 6 hr±15 min, 8 hr±15 min, 12 hr±15 min, 16 hr±15 min, 24 hr±15 min before the 2nd dose) Day 3 and Day 4: pre-3rd, -4th dose (-2 to 0 hr) Day 5: pre-5th dose (-2 to 0 hr), post-5th dose (1 hr±3 min, 2 hr±5 min, 3 hr±10 min, 4 hr±10 min, 6 hr±15 min, 8 hr±15 min, 12 hr±15 min, 16 hr±15 min, 24 hr±15 min, 36 hr±15 min, 48 hr±15 min, 72 hr±15 min, 96 hr±15 min)
Urine PK parameters: the amount of study drug excreted into urine and urine recovery rate (Ae%) in cohort 5
Time Frame: Day 1: pre-1st dose (-2-0 hr), post-1st dose (0-6 hr, 6-12 hr, 12-24 hr) Day 5: post-5th dose (0-6 hr, 6-12 hr, 12-24 hr, 24-36 hr, 36-48 hr, 48-72 hr, and 72-96 hr)
Area under the plasma concentration time curve from 0 to the last measurable concentration (AUC0-t) in cohort 6-8
Time Frame: Up to 6 days
Day 1: pre-1st dose (-2 to 0 hr), post-1st dose (1 hr±3 min, 2 hr±5 min, 3 hr±10 min, 4 hr±10 min, 6 hr±15 min, 8 hr±15 min, 12 hr±15 min, 16 hr±15 min, 24 hr±15 min before the 2nd dose) Day 3: pre-3rd dose (-2 to 0 hr), post-3rd dose (1 hr±3 min, 2 hr±5 min, 3 hr±10 min, 4 hr±10 min, 6 hr±15 min, 8 hr±15 min, 12 hr±15 min, 16 hr±15 min, 24 hr±15 min, 36 hr±15 min, 48 hr±15 min, 72 hr±15 min, 96 hr±15 min)
Area under the plasma concentration time curve from 0 to infinity (AUC0-inf) in cohort 6-8
Time Frame: Up to 6 days
Day 1: pre-1st dose (-2 to 0 hr), post-1st dose (1 hr±3 min, 2 hr±5 min, 3 hr±10 min, 4 hr±10 min, 6 hr±15 min, 8 hr±15 min, 12 hr±15 min, 16 hr±15 min, 24 hr±15 min before the 2nd dose) Day 3: pre-3rd dose (-2 to 0 hr), post-3rd dose (1 hr±3 min, 2 hr±5 min, 3 hr±10 min, 4 hr±10 min, 6 hr±15 min, 8 hr±15 min, 12 hr±15 min, 16 hr±15 min, 24 hr±15 min, 36 hr±15 min, 48 hr±15 min, 72 hr±15 min, 96 hr±15 min)
Maximum plasma concentration (Cmax) in cohort 6-8
Time Frame: Up to 6 days
Day 1: pre-1st dose (-2 to 0 hr), post-1st dose (1 hr±3 min, 2 hr±5 min, 3 hr±10 min, 4 hr±10 min, 6 hr±15 min, 8 hr±15 min, 12 hr±15 min, 16 hr±15 min, 24 hr±15 min before the 2nd dose) Day 3: pre-3rd dose (-2 to 0 hr), post-3rd dose (1 hr±3 min, 2 hr±5 min, 3 hr±10 min, 4 hr±10 min, 6 hr±15 min, 8 hr±15 min, 12 hr±15 min, 16 hr±15 min, 24 hr±15 min, 36 hr±15 min, 48 hr±15 min, 72 hr±15 min, 96 hr±15 min)
Trough plasma concentration (Cmin) in cohort 6-8
Time Frame: Up to 6 days
Day 1: pre-1st dose (-2 to 0 hr), post-1st dose (1 hr±3 min, 2 hr±5 min, 3 hr±10 min, 4 hr±10 min, 6 hr±15 min, 8 hr±15 min, 12 hr±15 min, 16 hr±15 min, 24 hr±15 min before the 2nd dose) Day 3: pre-3rd dose (-2 to 0 hr), post-3rd dose (1 hr±3 min, 2 hr±5 min, 3 hr±10 min, 4 hr±10 min, 6 hr±15 min, 8 hr±15 min, 12 hr±15 min, 16 hr±15 min, 24 hr±15 min, 36 hr±15 min, 48 hr±15 min, 72 hr±15 min, 96 hr±15 min)
Time at which maximum plasma concentration (Tmax) is observed in cohort 6-8
Time Frame: Up to 6 days
Day 1: pre-1st dose (-2 to 0 hr), post-1st dose (1 hr±3 min, 2 hr±5 min, 3 hr±10 min, 4 hr±10 min, 6 hr±15 min, 8 hr±15 min, 12 hr±15 min, 16 hr±15 min, 24 hr±15 min before the 2nd dose) Day 3: pre-3rd dose (-2 to 0 hr), post-3rd dose (1 hr±3 min, 2 hr±5 min, 3 hr±10 min, 4 hr±10 min, 6 hr±15 min, 8 hr±15 min, 12 hr±15 min, 16 hr±15 min, 24 hr±15 min, 36 hr±15 min, 48 hr±15 min, 72 hr±15 min, 96 hr±15 min)
Terminal elimination half-life (t1/2) in cohort 6-8
Time Frame: Up to 6 days
Day 1: pre-1st dose (-2 to 0 hr), post-1st dose (1 hr±3 min, 2 hr±5 min, 3 hr±10 min, 4 hr±10 min, 6 hr±15 min, 8 hr±15 min, 12 hr±15 min, 16 hr±15 min, 24 hr±15 min before the 2nd dose) Day 3: pre-3rd dose (-2 to 0 hr), post-3rd dose (1 hr±3 min, 2 hr±5 min, 3 hr±10 min, 4 hr±10 min, 6 hr±15 min, 8 hr±15 min, 12 hr±15 min, 16 hr±15 min, 24 hr±15 min, 36 hr±15 min, 48 hr±15 min, 72 hr±15 min, 96 hr±15 min)
Terminal elimination rate constant (λz) in cohort 6-8
Time Frame: Up to 6 days
Day 1: pre-1st dose (-2 to 0 hr), post-1st dose (1 hr±3 min, 2 hr±5 min, 3 hr±10 min, 4 hr±10 min, 6 hr±15 min, 8 hr±15 min, 12 hr±15 min, 16 hr±15 min, 24 hr±15 min before the 2nd dose) Day 3: pre-3rd dose (-2 to 0 hr), post-3rd dose (1 hr±3 min, 2 hr±5 min, 3 hr±10 min, 4 hr±10 min, 6 hr±15 min, 8 hr±15 min, 12 hr±15 min, 16 hr±15 min, 24 hr±15 min, 36 hr±15 min, 48 hr±15 min, 72 hr±15 min, 96 hr±15 min)
Urine PK parameters: the amount of study drug excreted into urine and urine recovery rate (Ae%) in cohort 6-8
Time Frame: Day 1: pre-1st dose (-2-0 hr), post-1st dose (0-4 hr, 4-8 hr, 8-12 hr, 12-16 hr, and 16-24 hr) Day 3: post-3rd dose (0-4 hr, 4-8 hr, 8-12 hr, 12-16 hr, 16-24 hr, 24-36 hr, 36-48 hr, 48-72 hr, and 72-96 hr)
Secondary Outcomes
- Difference on trough plasma concentration (Cmin) between cohort 1 and 3(pre-dose (-2 to 0 hr) and post-dose (1 hr±3 min, 2 hr±5 min, 3 hr±10 min, 4 hr±10 min, 6 hr±15 min, 8 hr±15 min, 12 hr±15 min, 16 hr±15 min, 24 hr±15 min, 36 hr±15 min, 48 hr±15 min, 72 hr±15 min, 96 hr±15 min))
- Difference on time at which maximum plasma concentration (Tmax) is observed between cohort 1 and 3(pre-dose (-2 to 0 hr) and post-dose (1 hr±3 min, 2 hr±5 min, 3 hr±10 min, 4 hr±10 min, 6 hr±15 min, 8 hr±15 min, 12 hr±15 min, 16 hr±15 min, 24 hr±15 min, 36 hr±15 min, 48 hr±15 min, 72 hr±15 min, 96 hr±15 min))
- Difference on terminal elimination half-life (t1/2) between cohort 1 and 3(pre-dose (-2 to 0 hr) and post-dose (1 hr±3 min, 2 hr±5 min, 3 hr±10 min, 4 hr±10 min, 6 hr±15 min, 8 hr±15 min, 12 hr±15 min, 16 hr±15 min, 24 hr±15 min, 36 hr±15 min, 48 hr±15 min, 72 hr±15 min, 96 hr±15 min))
- Difference on terminal elimination rate constant (λz) in cohort 6-8(pre-dose (-2 to 0 hr) and post-dose (1 hr±3 min, 2 hr±5 min, 3 hr±10 min, 4 hr±10 min, 6 hr±15 min, 8 hr±15 min, 12 hr±15 min, 16 hr±15 min, 24 hr±15 min, 36 hr±15 min, 48 hr±15 min, 72 hr±15 min, 96 hr±15 min))
- Difference on area under the plasma concentration time curve from 0 to the last measurable concentration (AUC0-t) between cohort 1 and 3(pre-dose (-2 to 0 hr) and post-dose (1 hr±3 min, 2 hr±5 min, 3 hr±10 min, 4 hr±10 min, 6 hr±15 min, 8 hr±15 min, 12 hr±15 min, 16 hr±15 min, 24 hr±15 min, 36 hr±15 min, 48 hr±15 min, 72 hr±15 min, 96 hr±15 min))
- Difference on area under the plasma concentration time curve from 0 to infinity (AUC0-inf) between cohort 1 and 3(pre-dose (-2 to 0 hr) and post-dose (1 hr±3 min, 2 hr±5 min, 3 hr±10 min, 4 hr±10 min, 6 hr±15 min, 8 hr±15 min, 12 hr±15 min, 16 hr±15 min, 24 hr±15 min, 36 hr±15 min, 48 hr±15 min, 72 hr±15 min, 96 hr±15 min))
- Difference on maximum plasma concentration (Cmax) between cohort 1 and 3(pre-dose (-2 to 0 hr) and post-dose (1 hr±3 min, 2 hr±5 min, 3 hr±10 min, 4 hr±10 min, 6 hr±15 min, 8 hr±15 min, 12 hr±15 min, 16 hr±15 min, 24 hr±15 min, 36 hr±15 min, 48 hr±15 min, 72 hr±15 min, 96 hr±15 min))