This will be a randomized, double-blind, single-dose, three-period balanced crossover study in adult healthy subjects. Each of the 18 subjects will be randomized to receive a treatment sequence consisting of each of the three treatments (FF 400 microgram (mcg), UMEC 500 mcg and FF 400 mcg/UMEC 500 mcg), in three consecutive periods, with a wash-out period of 7 to 10 days between the periods. The study will include a Screening period (28 days prior to first dose), Treatment period (3 single dose periods separated by two 7 to 10 days washout periods) and Follow-up period (7 to 14 days post last dose). The pharmacokinetic (PK) and safety assessments will be performed during the study at fixed timepoints.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
DOUBLE
Enrollment
18
FF will be available as 100 mcg strength administered as 4 inhalations from a DPI
UMEC will be available as 125 mcg strength administered as 4 inhalations from a DPI
FF/UMEC will be available as 100/125 mcg strength administered as 4 inhalations from a DPI
GSK Investigational Site
Baltimore, Maryland, United States
Maximum observed plasma concentration (Cmax) in plasma for FF and UMEC
The PK parameter Cmax will be calculated for FF/UMEC in combination and as monotherapies
Time frame: Period 1, 2 and 3: Day 1 (pre-dose, 5 minutes [mins], 15 mins, 30 mins, 45 mins, 1 hour (h), 1.5 h, 2 h, 3 h, 4 h, 6 h, 8 h, 12 h, and 16 h) and Day 2 (24 h)
Area under the concentration-time curve (AUC(0-t)), where t is time of last measurable concentration in plasma for FF and UMEC
The PK parameter AUC(0-t) will be calculated for will be calculated for FF/UMEC in combination and as monotherapies
Time frame: Period 1, 2 and 3: Day 1 (pre-dose, 5 mins, 15 mins, 30 mins, 45 mins, 1 h, 1.5 h, 2 h, 3 h, 4 h, 6 h, 8 h, 12 h, and 16 h) and Day 2 (24 h)
Area under the concentration-time curve from time zero (pre-dose) extrapolated to infinite time [AUC(0-inf)] in plasma for FF and UMEC, if data permits
The PK parameter AUC(0-inf) will be calculated for will be calculated for FF/UMEC in combination and as monotherapies
Time frame: Period 1, 2 and 3: Day 1 (pre-dose, 5 mins, 15 mins, 30 mins, 45 mins, 1 h, 1.5 h, 2 h, 3 h, 4 h, 6 h, 8 h, 12 h, and 16 h) and Day 2 (24 h)
Time of maximum observed concentration (tmax) in plasma for FF and UMEC
The FF and UMEC PK parameter in plasma will be calculated to compare the PK of FF/UMEC in combination with FF and UMEC monotherapies
Time frame: Period 1, 2 and 3: Day 1 (pre-dose, 5 mins, 15 mins, 30 mins, 45 mins, 1 h, 1.5 h, 2 h, 3 h, 4 h, 6 h, 8 h, 12 h, and 16 h) and Day 2 (24 h)
Time of last measurable concentration (tlast) in plasma for FF and UMEC
The FF and UMEC PK parameter in plasma will be calculated to compare the PK of FF/UMEC in combination with FF and UMEC monotherapies
Time frame: Period 1, 2 and 3: Day 1 (pre-dose, 5 mins, 15 mins, 30 mins, 45 mins, 1 h, 1.5 h, 2 h, 3 h, 4 h, 6 h, 8 h, 12 h, and 16 h) and Day 2 (24 h)
Plasma elimination half life (t½) in plasma for FF and UMEC, if data permits
The FF and UMEC PK parameter in plasma will be calculated to compare the PK of FF/UMEC in combination with FF and UMEC monotherapies
Time frame: Period 1, 2 and 3: Day 1 (pre-dose, 5 mins, 15 mins, 30 mins, 45 mins, 1 h, 1.5 h, 2 h, 3 h, 4 h, 6 h, 8 h, 12 h, and 16 h) and Day 2 (24 h)
Elimination rate constant (Lambda z) in plasma for FF and UMEC, if data permits
The FF and UMEC PK parameter in plasma will be calculated to compare the PK of FF/UMEC in combination with FF and UMEC monotherapies
Time frame: Period 1, 2 and 3: Day 1 (pre-dose, 5 mins, 15 mins, 30 mins, 45 mins, 1 h, 1.5 h, 2 h, 3 h, 4 h, 6 h, 8 h, 12 h, and 16 h) and Day 2 (24 h)
Apparent clearance (CL/F) in plasma for FF and UMEC, if data permits
The FF and UMEC PK parameter in plasma will be calculated to compare the PK of FF/UMEC in combination with FF and UMEC monotherapies
Time frame: Period 1, 2 and 3: Day 1 (pre-dose, 5 mins, 15 mins, 30 mins, 45 mins, 1 h, 1.5 h, 2 h, 3 h, 4 h, 6 h, 8 h, 12 h, and 16 h) and Day 2 (24 h)
Apparent volume of distribution (V/F) in plasma for FF and UMEC, if data permits
The FF and UMEC PK parameter in plasma will be calculated to compare the PK of FF/UMEC in combination with FF and UMEC monotherapies
Time frame: Period 1, 2 and 3: Day 1 (pre-dose, 5 mins, 15 mins, 30 mins, 45 mins, 1 h, 1.5 h, 2 h, 3 h, 4 h, 6 h, 8 h, 12 h, and 16 h) and Day 2 (24 h)
Cumulative amount excreted drug in urine (Ae) for UMEC
The UMEC PK parameter in urine will be calculated to compare the PK of UMEC when co-administered with FF; with UMEC as a monotherapy
Time frame: Period 1, 2 and 3: Day 1 (pre-dose, 0-6 h, 0-8 h, 0-12 h, 0-16 h) and Day 2(0-24 h)
Percent of dose excreted (% Fe) in urine for UMEC
The UMEC PK parameter in urine will be calculated to compare the PK of UMEC when co-administered with FF; with UMEC as a monotherapy
Time frame: Period 1, 2 and 3: Day 1 (pre-dose, 0-6 h, 0-8 h, 0-12 h, 0-16 h) and Day 2 (0-24 h)
Urine half life (urine t½) for UMEC, if data permits
The UMEC PK parameter in urine will be calculated to compare the PK of UMEC when co-administered with FF; with UMEC as a monotherapy
Time frame: Period 1, 2 and 3: Day 1 (pre-dose, 0-6 h, 0-8 h, 0-12 h, 0-16 h) and Day 2 (0-24 h)
Renal clearance (CLr) in urine for UMEC, if data permits
The UMEC PK parameter in urine will be calculated to compare the PK of UMEC when co-administered with FF; with UMEC as a monotherapy
Time frame: Period 1, 2 and 3: Day 1 (pre-dose, 0-6 h, 6-8 h, 8-12 h, 12-16 h) and Day 2(16-24 h)
Area under the concentration-time curve from time zero (pre-dose) to the time at which AUC is calculable for all subjects (AUC(0-t')), where t' is the time at which AUC is calculable for all the subjects
The PK parameter AUC(0-t') will be calculated for will be calculated for FF/UMEC in combination and as monotherapies
Time frame: Period 1, 2 and 3: Day 1 (pre-dose, 5 mins, 15 mins, 30 mins, 45 mins, 1 h, 1.5 h, 2 h, 3 h, 4 h, 6 h, 8 h, 12 h, and 16 h) and Day 2 (24 h)
Clinical Safety data assessed as number of adverse events (AE) in each treatment group
Safety and tolerability will be assessed by recording of AEs for subjects receiving FF/UMEC in combination compared with FF and UMEC monotherapies.
Time frame: Period 1 Day 1 dose to Follow up visit
Clinical laboratory measurements for each treatment group
Safety and tolerability will be assessed by measuring the clinical laboratory parameters which include hematology, clinical chemistry, routine urinalysis and additional parameters.
Time frame: Period 1, 2 and 3: Baseline (Day -1) and Day 2
Systolic and diastolic blood pressure for each treatment group
Safety and tolerability will be assessed by measuring vital signs which include systolic and diastolic blood pressure.
Time frame: Baseline (Day 1 pre-dose) and Day 2 of each treatment period; and Follow-up Visit
Heart rate for each treatment group
Safety and tolerability will be assessed by measuring vital signs which include heart rate.
Time frame: Baseline (Day 1 pre-dose) and Day 2 of each treatment period; and Follow-up Visit
12-lead electrocardiogram (ECG) for each treatment group
Safety and tolerability will be assessed by measuring ECG using an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT and QTc intervals.
Time frame: Baseline (Day 1 pre-dose) and Day 2 of each treatment period; and Follow-up Visit
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