This study investigates the safety, tolerability and PKs of GSK2838232 with and without Ritonavir, and to evaluate different formulations of GSK2838232 in healthy subjects. This study will evaluate higher single and RTV boosted doses to support continued clinical development of GSK2838232 at clinically relevant doses, and subsequently in those infected with HIV in a dose ranging phase 2 study. The study is conducted in 2 parts: Part A and Part B, study Part A and Part B may be conducted in parallel. Approximately 20 healthy subjects will be enrolled into the study, 8 in Part A and 12 in Part B. Part A is a double-blind, randomized, placebo-controlled, 4-period, single dose escalation design. Subjects will be randomized 3:1 to receive GSK2838232 or placebo. Subjects randomized to placebo will receive placebo in all four periods. Following completion of Period 2 PK assessments at 96hr post-dose, subjects will begin daily dosing of RTV 100mg for a total of 26 days. Part B is a randomized, open-label, unbalanced, 3-period, cross-over design; subjects will be randomized 1:1 to each sequence. The relative bioavailability of single 100mg doses of powder in a bottle (PIB) active pharmaceutical ingredient (API) of GSK2838232 versus PIB spray-dried dispersion (SDD) will be assessed. A single dose of GSK2838232 will co-administered on the 10th day of RTV dosing; RTV dosing will continue for an additional 4 days (total of 14 days). Subjects will have a screening visit within 30 days prior to first dose and a follow-up visit 7-14 days after the last dose.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
DOUBLE
Enrollment
20
GSK2838232 will be available as oral suspension dispersion in hydromellulose acetate succinate bulk powder/10, 20, 50, 200 and 500 mg in part A, while 100 mg in Part B. GSK2838232 will be administered orally once daily (QD) as single doses in the morning following an overnight fast of at least 10 hours.
GSK2838232 will be available as oral suspension bulk powder/100 mg in Part B. GSK2838232 will be administered orally QD as single doses in the Morning following an overnight fast of at least 10 hours.
Matching placebo of Suspension to active dose, administered orally QD as single doses in the morning following an overnight fast of at least 10 hours.
Ritonavir will be available as white film-coated ovaloid tablets of 100 mg tablet/100mg. Ritonavir will be administered orally, once daily in Part A, Period 3 Days 1-14 and Period 4 from Days 1-12 and will be administer orally once daily in Part B for 9 days prior to dosing in Period 3 and on Days 10-14 of Period 3.
GSK Investigational Site
Baltimore, Maryland, United States
Adverse events (AEs) assessments
Safety was assessed by monitoring AE and serious AEs (SAE). AEs and SAEs will be collected from the start of Study Treatment until the follow-up contact
Time frame: Up to approximately 7 weeks
Safety assessed by laboratory evaluations
Laboratory evaluations will include hematology, clinical chemistry, urinalysis assessments
Time frame: Up to approximately 7 weeks
Vital signs assessments
Vital signs will be measured in semi-supine position after 10 minutes rest and will include systolic and diastolic blood pressure and pulse rate.
Time frame: Up to approximately 7 weeks
Electrocardiogram (ECG) parameters assessments
Triplicate or Single 12-lead ECGs will be obtained at each timepoint during the study after a 10 minute rest using an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, and QTc intervals.
Time frame: Up to approximately 7 weeks
Composite PK profile of GSK2838232, , with and without RTV for Part A and Part B
PK assessments 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 over the dosing interval (AUC 0-t), concentration at 24 hours post dose (C24), oral clearance (CL/F), maximum observed concentration (Cmax), last quantifiable concentration (Clast), time of occurrence of Cmax (tmax), time of last observed concentration (tlast), terminal phase half-life (t1/2), and time of first quantifiable concentration (tlag).
Time frame: During Part A: Day 1 to Day 5 (Period 1 & 2), Day 10-Day 15 (Period 3), Day 8 - Day 13 (Period 4). During Part B: Day 1 to Day 4 (Period 1 & 2), Day 10-Day 14 (Period 3)
Composite PK profile of GSK2838232 to assess the relative bioavailability of the PIB API suspension versus PIB SDD suspension (Part B)
PK assessments will include: GSK2838232 AUC(0-infinity), Cmax
Time frame: During Part B: Day 1 to Day 4 (Period 1 & 2), Day 10-Day 14 (Period 3)
Composite PK profile of GSK2838232 to assess single dose proportionality of GSK2838232 with and without steady-state RTV (Part A)
PK assessments will include: GSK2838232 AUC(0 - infinity), AUC(0-t) and Cmax
Time frame: During Part A: Day 1 to Day 5 (Period 1 & 2), Day 10-Day 15 (Period 3), Day 8 - Day 13 (Period 4).
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