This will be the first time GSK1325756 Solution for Infusion formulation that has been administered to humans. Prior studies have been performed with oral GSK1325756. The primary objectives of this study are to obtain information on the safety, tolerability, and pharmacokinetics (PK) of single and twice daily intravenous (IV) administration of GSK1325756 in healthy subjects. In Part A, single, escalating doses will be given in the same cohort of subjects after a seven day washout. In addition, the study will evaluate the absolute bioavailability of a single dose of the current oral tablet formulation as compared to the IV formulation in Part A. In Part B, twice daily (BID) intravenous dose administration will be given for 5 days (9 total doses) in two separate cohorts of subjects. Data from this study will provide understanding of the safety, tolerability, and PK of intravenously administered GSK1325756 twice daily to guide dose selection in future clinical studies in patients with viral respiratory tract infections
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
DOUBLE
Enrollment
24
Solution containing 2 mg/mL GSK1325756 in sterile water for injection, to be administered intravenously.
Solution containing sterile water for injection matching GSK1325756 solution, to be administered intravenously.
A white film coated tablet containing 50 mg GSK1325756 to be administered orally.
A white film coated tablet matching GSK1325756 tablet, to be administered orally.
GSK Investigational Site
Overland Park, Kansas, United States
Number of subjects with adverse events (AEs)
An AE is any untoward medical occurrence in a clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product
Time frame: Part A and Part B: from Day -1 until 7 to 10 days post-last dose
Changes over time in clinical laboratory evaluations from pre-dose values
Clinical laboratory assessments will include hematology, clinical chemistry, urinalysis parameters
Time frame: Part A and Part B: from Day -1 until 7 to 10 days post-last dose
Changes over time in vital signs from pre-dose values
Vital sign measurements will include systolic and diastolic blood pressure and pulse rate
Time frame: Part A and Part B: from Day -1 until 7 to 10 days post-last dose
Changes over time in electrocardiogram (ECG) parameters from pre-dose values
12-lead ECGs will be obtained at each timepoint
Time frame: Part A and Part B: from Day -1 until 7 to 10 days post-last dose
GSK1325756 PK parameters following single dose administration in Part A and on Day 1 of Part B
PK parameters will 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 time t \[AUC(0-t)\], area under the concentration-time curve from time zero (pre-dose) to 24 hours \[AUC(0-24)\], maximum observed concentration (Cmax), time to maximum observed concentration (tmax), observed concentration at 24 hours post-dose (C24), terminal half-life (t1/2), time of last measurable concentration (tlast), clearance (CL) and volume of distribution (Vz)
Time frame: Part A: Pre-dose, 0.5 hour (hr), 1hr (end of infusion/post oral dose), 1.5, 2, 3, 4, 8, 12, 24hrs post-dose in each treatment period.
GSK1325756 PK parameters following repeat dose administration (Part B, Day 5)
PK parameters will include area under the concentration-time curve from time zero (pre-dose) to the end of the dosing interval \[AUC(0-tau)\], concentration at the end of the dosing interval (Ctau), Cmax, tmax, t1/2, Volume of distribution at steady-state (Vdss), and oral clearance (CL/F)
Time frame: Part B: Day 5 at pre-dose, 0.5, 1hr (end of infusion), 1.5, 2, 3, 4, 8, 12 and 24 hrs post-dose
GSK1325756 PK parameters following single and repeat IV dose administration to assess dose proportionality
PK parameters will include AUC(0-infinity), AUC(0-t), Cmax, and C24 following single IV dose administration (Part A) and AUC(0-tau), Ctau, and Cmax following repeated IV dose administration (Part B)
Time frame: Part A: Pre-dose, 0.5hr, 1hr (end of infusion/post oral dose), 1.5, 2, 3, 4, 8, 12, 24hrs post-dose. Part B: Day 1 and Day 5: pre-dose, 0.5, 1hr (end of infusion), 1.5, 2, 3, 4, 8, 12 and (Day 5 only) 24 hrs post-dose. Day 2-4: pre-dose (each dose)
GSK1325756 PK parameters following single IV and oral dose administration of a given dose of GSK1325756 (Part A) to determine the absolute bioavailability
PK parameters will include AUC(0-infinity), AUC(0-t), Cmax and tmax
Time frame: Part A: Pre-dose, 0.5hr, 1hr (end of infusion/post oral dose), 1.5, 2, 3, 4, 8, 12, 24hrs post-dose
GSK1325756 accumulation ratio
GSK1325756 AUC(0-tau), Cmax, and Ctau on the last day of dosing will be compared to area under the concentration-time curve from time zero (pre-dose) to 12 hours \[AUC(0-12)\], Cmax, and observed concentration at 12 hours post-dose (C12) on Day 1 to estimate accumulation ratio
Time frame: Part A: Pre-dose, 0.5hr, 1hr (end of infusion/post oral dose), 1.5, 2, 3, 4, 8, 12, 24hrs post-dose Part B: Day 1 and Day 5: pre-dose, 0.5, 1hr (end of infusion), 1.5, 2, 3, 4, 8, 12 and (Day 5 only) 24 hrs post-dose. Day 2-4: pre-dose (each dose)
GSK1325756 time invariance
GSK1325756 AUC(0-tau) on the last day of dosing in Part B, will be compared to AUC(0-infinity) on Day 1 of Part A to evaluate time invariance
Time frame: Part A: Pre-dose, 0.5hr, 1hr (end of infusion/post oral dose), 1.5, 2, 3, 4, 8, 12, 24hrs post-dose Part B: Day 1 and Day 5: pre-dose, 0.5, 1hr (end of infusion), 1.5, 2, 3, 4, 8, 12 and (Day 5 only) 24 hrs post-dose. Day 2-4: pre-dose (each dose)
GSK1325756 Pre-dose concentrations (C12/Ctau) on Day 2 through 4
GSK1325756 Pre-dose concentrations on Day 2 through 4 will be used to assess the achievement of steady state of GSK1325756 following repeat administration (Part B)
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Time frame: Part B: Day 2 to Day 4 (pre-dose; each dose)
Correlation between PK parameters and various safety parameters, if appropriate
Time frame: Part A and Part B: from Day -1 until 7 to 10 days post-last dose