Infections, Respiratory Tract
Conditions
Keywords
GSK1325756, Safety, Bioavailability, Pharmacokinetics
Brief summary
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
Interventions
DRUGGSK1325756 Solution
Solution containing 2 mg/mL GSK1325756 in sterile water for injection, to be administered intravenously.
DRUGGSK1325756 Solution Matching Placebo
Solution containing sterile water for injection matching GSK1325756 solution, to be administered intravenously.
DRUGGSK1325756 Tablet
A white film coated tablet containing 50 mg GSK1325756 to be administered orally.
DRUGGSK1325756 Tablet Matching Placebo
A white film coated tablet matching GSK1325756 tablet, to be administered orally.
Sponsors
GlaxoSmithKline
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
* Males/females aged between 18 and 65 years of age inclusive, at the time of signing the informed consent. * Healthy as determined by a responsible and experienced physician, based on a medical evaluation including (medical history, physical examination, laboratory tests and ECG). A subject with a clinical abnormality or laboratory parameter(s) which is/are not specifically listed in the inclusion or
Exclusion criteria
, outside the reference range for the population being studied may be included only if the Investigator agrees and documents that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures * Body weight \>=60 kilograms (kg) for men and \>=45 kg for women; and Body Mass Index (BMI) within the range 19 to 32 kg/square meter (m\^2) (inclusive). * A female subject is eligible to participate if she is of: Non-childbearing potential defined as pre-menopausal females with a documented tubal ligation or hysterectomy \[for this definition, documented refers to the outcome of the investigator's/designee's review of the subject's medical history for study eligibility, as obtained via a verbal interview with the subject or from the subject's medical records\]; or postmenopausal defined as 12 months of spontaneous amenorrhea \[in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) \> 40 milli-international unit (MIU)/milliliter (mL) and estradiol \<40 picograms (pg)/mL (\<147 picomoles \[pmol\]/liter \[L\]) is confirmatory\]. * Male subjects with female partners of child-bearing potential must agree to use one of the acceptable contraception methods. This criterion must be followed from the time of the first dose of study medication until 90 days following the last dose. * Alanine aminotransferase (ALT), alkaline phosphatase and bilirubin \<=1.5 x upper limit of normal (ULN) (isolated bilirubin \>1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin \<35%). * Based on a single ECG obtained over a brief recording period: corrected QT interval (QTc) \<450 milliseconds (msec); or QTc \<480 msec in subjects with Bundle Branch Block. * Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| GSK1325756 PK parameters following repeat dose administration (Part B, Day 5) | 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 | 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) |
| Number of subjects with adverse events (AEs) | Part A and Part B: from Day -1 until 7 to 10 days post-last dose | 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 |
| Changes over time in clinical laboratory evaluations from pre-dose values | Part A and Part B: from Day -1 until 7 to 10 days post-last dose | Clinical laboratory assessments will include hematology, clinical chemistry, urinalysis parameters |
| Changes over time in vital signs from pre-dose values | Part A and Part B: from Day -1 until 7 to 10 days post-last dose | Vital sign measurements will include systolic and diastolic blood pressure and pulse rate |
| Changes over time in electrocardiogram (ECG) parameters from pre-dose values | Part A and Part B: from Day -1 until 7 to 10 days post-last dose | 12-lead ECGs will be obtained at each timepoint |
| GSK1325756 PK parameters following single dose administration in Part A and on Day 1 of Part B | 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. | 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) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| GSK1325756 PK parameters following single and repeat IV dose administration to assess dose proportionality | 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) | 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) |
| GSK1325756 PK parameters following single IV and oral dose administration of a given dose of GSK1325756 (Part A) to determine the absolute bioavailability | Part A: Pre-dose, 0.5hr, 1hr (end of infusion/post oral dose), 1.5, 2, 3, 4, 8, 12, 24hrs post-dose | PK parameters will include AUC(0-infinity), AUC(0-t), Cmax and tmax |
| GSK1325756 accumulation ratio | 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 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 |
| GSK1325756 time invariance | 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 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 |
| GSK1325756 Pre-dose concentrations (C12/Ctau) on Day 2 through 4 | Part B: Day 2 to Day 4 (pre-dose; each dose) | 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) |
| Correlation between PK parameters and various safety parameters, if appropriate | Part A and Part B: from Day -1 until 7 to 10 days post-last dose | — |
Countries
United States
Outcome results
None listed