This study is the first administration of GSK2849466 in humans. This will be a single centre, randomized, double-blind, placebo-controlled study, to investigate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of GSK2849466, given as single and repeat oral doses up to 14 days to healthy male subjects. Part A will be a randomized placebo controlled and 4-way crossover study. It will include two cohorts of 8 subjects each. In each cohort there will be 4 study periods each approximately of 1 week including 6 days of washout. Each subject will receive a total of 3 active doses as ascending single oral dose of GSK2849466 and 1 placebo dose during the course of their participation in the study. The first ("bridging dose") dose provided to subjects in Cohort 2 will be the same as the last dose provided to subjects in Cohort 1. The single doses of GSK2849466 planned in Part A of this study are: 0.01, 0.03, 0.1, and 0.3 milligram (mg) in Cohort 1 and 0.3, 1, 3, and 10 mg in Cohort 2. In cohorts 1 and 2 all available safety, tolerability, and PK data will be reviewed prior to each dose escalation. The dosing schedule in Part A may be adjusted to expand a cohort or to add an additional cohort(s) in order to further evaluate additional doses or repeat evaluation of a dose level already studied. Part B will be a randomized placebo controlled, parallel group study. It will include three cohorts of 12 subjects each. Each subject will receive repeat doses of GSK2849466 over 14 days. The doses chosen for Part B will be based on the safety, tolerability, and PK data from Part A. Subjects in Cohort 4 (and/or an another cohort \[s\] as determined based on Part A PK data) will be dosed in the fasted state on Days 1 and 14 and in the fed state on Day 7 when subjects will receive a standard meal 30 minutes prior to dosing. Part B will provide sufficient safety and tolerability data to bridge to longer duration studies. The study duration, including screening and follow-up, is not expected to exceed 70 days for subjects in the study.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
OTHER
Masking
DOUBLE
Enrollment
17
GSK2849466 will be available as capsules of dose strengths 0.01, 0.1, 1.0, and 2.5 mg.
Matching placebo capsules will be available.
GSK Investigational Site
Baltimore, Maryland, United States
Safety and tolerability of single ascending doses GSK2849466 as assessed by number of subjects with adverse events (AE)s
Safety and tolerability parameters will include recording of AEs, throughout the study.
Time frame: 28 days
Safety and tolerability of repeat doses of GSK2849466 as assessed by number of subjects with AEs
Safety and tolerability parameters will include recording of AEs, throughout the study.
Time frame: 14 days
Safety and tolerability of single ascending doses of GSK2849466 as assessed by change from Baseline in electrocardiogram (ECG) readings
Safety and tolerability parameter will include the ECG readings at Baseline and at end of the study.
Time frame: 28 days
Safety and tolerability of repeat doses of GSK2849466 as assessed by change from Baseline in ECG readings
Safety and tolerability parameter will include the ECG readings at Baseline and at end of the study.
Time frame: 14 days
Safety and tolerability of single ascending doses of GSK2849466 as assessed by change from Baseline in clinical monitoring of blood pressure
Safety and tolerability parameters will include blood pressure readings at Baseline and at end of the study.
Time frame: 28 days
Safety and tolerability of repeat doses of GSK2849466 as assessed by change from Baseline in clinical monitoring of blood pressure
Safety and tolerability parameters will include blood pressure readings at Baseline and at end of the study.
Time frame: 14 days
Safety and tolerability of single ascending doses of GSK2849466 as assessed by change from Baseline in heart rate
Safety and tolerability parameters will include heart rate at Baseline and at end of the study.
Time frame: 28 days
Safety and tolerability of repeat doses of GSK2849466 as assessed by change from Baseline in heart rate
Safety and tolerability parameters will include heart rate at Baseline and at end of the study.
Time frame: 14 days
Safety and tolerability of GSK2849466 as assessed by change from Baseline in cardiac telemetry
Safety and tolerability parameters will include cardiac telemetry recording at Baseline and at end of the study.
Time frame: Part A-Day 1 continuous at least 12 hours post-dose of each dosing session; Part B-Day 1, 4, 7, 10 and 14 continuous at least 8 hours post-dose
Safety and tolerability of single ascending doses of GSK2849466 as assessed by change from Baseline in laboratory assessments
Safety and tolerability parameters will include laboratory values at Baseline and at end of the study.
Time frame: 28 days
Safety and tolerability of repeat doses of GSK2849466 as assessed by change from Baseline in laboratory assessments
Safety and tolerability parameters will include laboratory values at Baseline and at end of the study.
Time frame: 14 days
Area under the time-concentration curve from time zero (pre-dose) to last time of quantifiable concentration (AUC(0-t)) and AUC from zero to infinity (AUC(0-inf)) following single doses of GSK2849466
The AUC(0-t) and AUC(0-inf) for GSK2849466 will be assessed following single doses of GSK2849466.
Time frame: 2 days of each treatment period in Part A: Day 1-0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 12 hours post dose; Day 2-24 hours post Day 1 dose.
Maximum concentration (Cmax) following single doses of GSK2849466
The Cmax of GSK2849466 will be assessed following single doses of GSK2849466.
Time frame: 2 days of each treatment period in Part A: Day 1-0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 12 hours post dose; Day 2-24 hours post Day 1 dose.
Time to maximum observed plasma drug concentration (Tmax) following single doses of GSK2849466
The Tmax for GSK2849466 will be assessed following single doses of GSK2849466.
Time frame: 2 days of each treatment period in Part A: Day 1-0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 12 hours post dose; Day 2-24 hours post Day 1 dose.
Terminal half-life (t1/2) following single doses of GSK2849466
The t1/2 for GSK2849466 will be assessed following single doses of GSK2849466.
Time frame: 2 days of each treatment period in Part A: Day 1-0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 12 hours post dose; Day 2-24 hours post Day 1 dose.
The AUC(0-t), AUC(0-inf)) and AUC from time zero to the end of the dosing interval at steady state AUC(0-tau) following repeat doses of GSK2849466
The AUC(0-t), AUC(0-inf) and AUC(0-tau) following repeat doses of GSK2849466 with and without food (Cohort 4 and/or another cohort(s) as determined based on Part A PK data) will be assessed in Part B of the study.
Time frame: Part B (all cohorts): Day 1, 2, 14, 15(24 hours serial sampling); Day 4, 5, 6, 7 (pre dose sampling). Part B (Cohort 4): Day 7 and 8 (24 hours serial sampling) and no PK samples on Day 8 if fasted on Day 7.
The Cmax following repeat doses of GSK2849466
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The Cmax following repeat doses of GSK2849466 with and without food (Cohort 4 and/or another cohort(s) as determined based on Part A PK data) will be assessed in Part B of the study.
Time frame: Part B (all cohorts): Day 1, 2, 14, 15(24 hours serial sampling); Day 4, 5, 6, 7 (pre dose sampling). Part B (Cohort 4): Day 7 and 8 (24 hours serial sampling) and no PK samples on Day 8 if fasted on Day 7.
The Tmax following repeat doses of GSK2849466
The Tmax following repeat doses of GSK2849466 with and without food (Cohort 4 and/or another cohort(s) as determined based on Part A PK data) will be assessed in Part B of the study.
Time frame: Part B (all cohorts): Day 1, 2, 14, 15(24 hours serial sampling); Day 4, 5, 6, 7 (pre dose sampling). Part B (Cohort 4): Day 7 and 8 (24 hours serial sampling) and no PK samples on Day 8 if fasted on Day 7.
The t1/2 following repeat doses of GSK2849466
The t1/2 following repeat doses of GSK2849466 with and without food (Cohort 4 and/or another cohort(s) as determined based on Part A PK data) will be assessed in Part B of the study.
Time frame: Part B (all cohorts): Day 1, 2, 14, 15(24 hours serial sampling); Day 4, 5, 6, 7 (pre dose sampling). Part B (Cohort 4): Day 7 and 8 (24 hours serial sampling) and no PK samples on Day 8 if fasted on Day 7.
The estimation of an accumulation ratio following repeat doses of GSK2849466
The estimation of an accumulation ratio following repeat doses of GSK2849466 with and without food (Cohort 4 and/or another cohort(s) as determined based on Part A PK data) will be assessed in Part B of the study.
Time frame: Part B (all cohorts): Day 1, 2, 14, 15(24 hours serial sampling); Day 4, 5, 6, 7 (pre dose sampling). Part B (Cohort 4): Day 7 and 8 (24 hours serial sampling) and no PK samples on Day 8 if fasted on Day 7.