This will be a randomized, open-label, sequential, single dose, 4-period crossover study. This study is being conducted to measure the relative bioavailability of the original gelatin capsule (GC) formulation and two new formulations (hydroxypropyl-methylcellulose \[HPMC\] capsule and enteric coated tablet \[ECT\]) of afuresertib (AFU), in the fed and fasted state. The study will be composed of Screening, Treatment, and Follow-up Periods. Screening assessments to determine subject eligibility will be performed within 3 weeks prior to the first dose of study drug in the Treatment Period. Eligible subjects will be randomized to receive 4 of the 6 possible study treatments (A: AFU GC administered in a fasted state, B: AFU GC administered in a fed state, C: AFU HPMC capsule administered in a fasted state, D: AFU HPMC capsule administered in a fed state, E: AFU ECT administered in a fasted state, F: AFU ECT administered in a fed state) in 4 treatment periods (one per treatment period). Subjects will receive a single dose of one of the six study treatments (A, B, C, D, E, F) on Day 1 of each Dosing Period, according to one of the 6 treatment sequences (CEDA, EFAB, ABFC, BDCE, FCBD, DAEF). There will be a minimum of 10 Day washout period between the doses administered in each Treatment Period. A Follow-up visit will be conducted within 10-14 days after the last dose. A subject's total time involved in the study will be approximately 9 weeks. At least 36 subjects will be enrolled in the study, to ensure that at least 6 subjects will be randomized to receive each treatment sequence.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
36
White opaque hard gelatin capsule containing afuresertib 25 mg. Subjects will receive single oral dose of afuresertib GC administered in fasted state
White opaque HPMC capsule containing afuresertib 25 mg. Subjects will receive single oral dose of afuresertib HPMC capsule administered in fasted state
White to off white, round, biconvex coated tablet containing afuresertib 25 mg. Subjects will receive single oral dose of afuresertib ECT administered in fasted state
White opaque hard gelatin capsule containing afuresertib 25 mg. Subjects will receive single oral dose of afuresertib GC administered in fed state
White opaque HPMC capsule containing afuresertib 25 mg. Subjects will receive single oral dose of afuresertib HPMC capsule administered in fed state
White to off white, round, biconvex coated tablet containing afuresertib 25 mg. Subjects will receive single oral dose of afuresertib ECT administered in fed state
GSK Investigational Site
Melbourne, Victoria, Australia
Composite of plasma pharmacokinetics (PK) parameters of afuresertib, following administration with and without food
Relative bioavailability of afuresertib after single dose of a GC, HPMC capsule and ECT, with and without high fat/calorie meal, will be determined by the following PK parameters: Area under the plasma concentration time curve- from time zero (pre-dose) to infinite time \[AUC(0-inf)\] and from time zero (pre-dose) to last time of quantifiable concentration \[AUC(0-t)\], maximum observed plasma concentration (Cmax), time to Cmax (tmax), observed plasma concentration at 24 hours (C24), and minimal observed plasma concentration (Ct)
Time frame: PK samples will be collected at Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 24, 48, and 72 hours post-dose in each dosing period
Safety and tolerability of afuresertib as assessed by number of subjects with adverse events (AEs)
AEs will be collected from the start of Study Treatment and until the Follow-up contact
Time frame: Up to 9 weeks
Safety and tolerability of afuresertib as assessed by clinical laboratory tests
Hematology, clinical chemistry and urinalysis parameters will be measured
Time frame: Up to 9 weeks
Safety and tolerability of afuresertib as assessed by concomitant medications review
Time frame: Up to 9 weeks
Safety and tolerability of afuresertib as assessed by electrocardiograms (ECG) measurements
Triplicate 12-lead ECGs will be collected at Screening; on Day 1 and Day 3 of each Dosing Period; and at Follow-up
Time frame: Up to 9 weeks
Safety and tolerability of afuresertib as assessed by vital signs measurement
Vital sign measurements will include systolic and diastolic blood pressure and pulse rate
Time frame: Up to 9 weeks
Change in phosphoAKT (pAKT) levels in peripheral blood samples following administration of a gelatin capsule, HPMC capsule and ECT
The potential relationship between plasma PK and pharmacodynamic biomarker changes (pAKT) of each formulation will be evaluated
Time frame: Pre-dose and 2, 12, and 24 hours post-dose in each dosing period.
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