GSK2878175 is a site IV NS5B non-nucleoside inhibitor (NNI) being developed for the treatment of chronic HCV infection. This study represents the first administration of GSK2878175 in humans to define safety, tolerability, and pharmacokinetics (PK) following single and repeat doses of GSK2878175 in healthy subjects. This is a Phase 1, randomized, single-blind, placebo-controlled, dose escalation study to determine the safety, tolerability, and PK profile of GSK2878175 in single (Part 1) and repeat doses (Part 2) in healthy subjects. In addition the study will explore the effect of a moderate (30%) fat meal on single dose PK endpoints in healthy subjects.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
SINGLE
Enrollment
47
Round tablets (5.0mg) given once daily single and repeated (to 7 days), Oral dose.
Visually matching GSK2878175
GSK Investigational Site
Randwick, New South Wales, Australia
Safety as assessed by the collection of adverse events (AEs).
AEs will be collected from the start of Study Treatment and until 7-14 days post last-dose (at follow up).
Time frame: Screening to 7-14 days post last-dose
Safety as assessed by hematology, clinical chemistry, urinalysis, vital signs, electrocardiogram (ECG) intervals, ECG rhythm telemetry, pulmonary function tests, respiratory rate and lung auscultation.
Absolute values and changes over time of hematology, clinical chemistry, urinalysis, vital signs (blood pressure \[BP\], FSH/Estradiol (Women), Urine β-hCG (Women) temperature, and heart rate), 12 LED ECG, and Holter monitoring, ECG intervals, ECG rhythm, and telemetry will be measured. Telemetry is the continuous monitoring of a subject's heart rate and rhythm from a remote location. Pulmonary function testing includes a group of tests that measure how well the lung is functioning.
Time frame: Pre-dose to 7-14 days post last-dose
Composite of pharmacokinetics (PK) parameters following single dose administration of GSK2878175.
PK parameters include: area under the concentration-time curve from time zero (pre-dose) extrapolated to infinite time (AUC \[0-infinity\]), area under the concentration-time curve from time zero (pre-dose) to last time of quantifiable concentration (AUC \[0-t\]), maximum observed concentration (Cmax), time to maximum observed concentration (tmax), observed concentration at 24hour post-dose (C24), lag time before observation of drug concentrations in sampled matrix (tlag), terminal half-life (t1/2), apparent oral clearance (CL/F).
Time frame: Part 1 and Day 1for Part 2
Composite of PK parameters following repeat dose administration of GSK2878175.
PK parameters include: AUC (0-infinity), AUC (0-t), Cmax, and Ctau (Pre-dose trough concentration at the end of the dosing interval),tmax, tlag, t1/2, CL/F
Time frame: on Part 2 Day 7
Dose proportionality of GSK2878175 PK parameters following single and repeat administration
GSK2878175 PK parameters: AUC (0-infinity), AUC (0-t), Cmax, and Ctau (Pre-dose trough concentration at the end of the dosing interval),tmax, tlag, t1/2
Time frame: Pre-dose, Day1 and Day 7
The effect of a moderate fat/caloric meal on the relative bioavailability of a given single dose of GSK2878175
GSK2878175 PK parameters: AUC (0-infinity), AUC (0-t), Cmax, and Ctau (Pre-dose trough concentration at the end of the dosing interval), tmax, tlag, t1/2, with and without moderate fat/calorie meal (Part 1).
Time frame: Pre-dose, Day1
Estimate GSK2878175 accumulation and time invariance
GSK2878175 AUC(0 t), Cmax, and Ctau on the last day of dosing compared to AUC(0-24), Cmax, and C24 on Day 1 to estimate accumulation ratio (R) and GSK2878175 AUC(0 t) on the last day of dosing compared to AUC(0 infinity) on Day 1 to evaluate time invariance (Part 2)
Time frame: Pre-dose, Day1 and Day 7
To assess attainment of steady state following repeat administration
Pre-dose concentrations on Day 3 through 7 and Ctau on Day 7 to assess the achievement of steady state of GSK2878175 following repeat administration (Part 2).
Time frame: Pre-dose, Day 1 and Day 7
To describe exposure-response relationships for various safety parameters, if appropriate.
Correlation between PK parameters and various safety parameters, if appropriate
Time frame: Pre-dose, Day1 and Day 7
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