The proposed study, 200207 is a double blind, placebo controlled, single and repeat dose escalation study to investigate the safety, tolerability and PK of GSK2838232 alone and when co-administered with RTV 100 milligram (mg) Once daily (QD). This study will enable future clinical development of GSK2838232 in healthy subjects and in a Phase IIa proof of concept study in Human Immunodeficiency Virus (HIV) infected patients. This study is a single and repeat dose escalation study and will be conducted as two Parts. Part A will evaluate GSK2838232 20 mg and 50 mg administered QD for 8 days and Part B will evaluate GSK2838232 10 mg, 20 mg, and 50 mg, co-administered with RTV 100 mg, QD for 11 days. The extended period of dosing is to account for the longer terminal phase half-life of GSK2838232 when given with RTV. Dose cohorts will be enrolled sequentially; enrollment into a cohort will commence following review of interim PK and safety data from at least 4 subjects in the preceding cohort. Subjects in both parts will have a screening visit within 30 days prior to first dose and a follow-up visit 7-14 days after the last dose. Maximum duration of study participation will be approximately 7 weeks. Approximately 40 healthy subjects will be enrolled, 8 subjects/cohort. Subjects will be randomized 3:1 to receive GSK2838232 or placebo.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
DOUBLE
Enrollment
24
GSK2838232 will be available as oral suspension dispersion in hydromellulose acetate succinate bulk powder/10, 20 and 50 mg which is to be administered orally QD for 8 days (Part A) or 11 days (Part B), morning dose, following an overnight fast of at least 10 hours
Matching placebo of Suspension to active dose, administered orally QD for 8 days (Part A) or 11 days (Part B), morning dose, following an overnight fast of at least 10 hours
Ritonavir will be available as white film-coated ovaloid tablets of 100 mg tablet/100mg to be administer orally, QD
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 pharmacokinetic profile of GSK2838232, , with and without RTV for Part A and Part B
PK assessments will include: On Day 1: Area under the concentration-time curve over the dosing interval (AUC\[0 tau\], Maximum observed concentration (Cmax), Pre-dose (trough) concentration at the end of the dosing interval (Ctau), time of occurrence of Cmax (tmax), lag time before observation of drug concentrations in sampled matrix (tlag), on Day 8 (Part A) or Day 11 (Part B): AUC(0-tau), Cmax, Ctau, tmax, tlag, terminal phase half-life (t1/2), last observed quantifiable concentration (Clast), time of last quantifiable concentration (tlast), Apparent clearance following oral dosing (CL/F).
Time frame: Up to 144 hours post dose of Day 11
Composite pharmacokinetic profile of GSK2838232 to dose proportionality with and without RTV
GSK2838232 AUC(0-tau), Cmax, Ctau
Time frame: Up to Day 17
Composite pharmacokinetic profile to assess accumulation of GSK2838232 with and without RTV
Accumulation will also be evaluated for each treatment by determining the ratio of Day 8 (Part A) or Day 11 (Part B) to Day 1 AUC(0 tau) (ratio of \[AUC{0-tau}\]), Cmax (R\[Cmax\]), and Ctau (R\[Ctau\])
Time frame: Up to Day 17
Pharmacokinetic profile to assess time to steady-state of GSK2838232 with and without RTV
Pre-dose concentrations on Day 2-8 (Part A) and Day 2-11 (Part B)
Time frame: Up to Day 17
Pharmacokinetic profile to compare the pharmacokinetics of GSK2383232 with and without RTV
GSK2838232 AUC(0-tau), Cmax, and Ctau
Time frame: Up to Day 17
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