GSK2269557 is being developed as an anti-inflammatory and anti-infective agent for the treatment of inflammatory airways diseases. This is the first study using a new formulation of GSK2269557 in healthy subjects and will evaluate the safety, tolerability and PK of a single dose of GSK2269557. Data derived from this study will inform on the PK profile and systemic exposure expected during Phase 2b. Approximately twelve healthy subjects will be randomized to receive a single dose of GSK2269557 750 micrograms (µg) or a single dose of GSK2269557 500 µg via the ELLIPTA® dry powder inhaler (DPI) formulated in a blend containing 0.4 percent magnesium stearate (MgSt) in 1:1 ratio. This randomized, parallel group study will be carried out in 3 phases, including screening phase, treatment phase and follow-up phase. The total study duration for each subject will be up to 6 weeks. ELLIPTA is a registered trademark of GlaxoSmithKline group of companies.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
DOUBLE
Enrollment
12
GSK2269557 is a potent and highly selective inhaled Phosphoinositide 3 Kinase delta inhibitor. Single dose of GSK2269557 500 µg will be administered to randomized subjects via inhalation route using ELLIPTA DPI.
GSK2269557 is a potent and highly selective inhaled Phosphoinositide 3 Kinase delta inhibitor. Single dose of GSK2269557 750 µg will be administered to randomized subjects via inhalation route using ELLIPTA DPI.
GSK Investigational Site
Cambridge, United Kingdom
Mean GSK2269557 Plasma Concentration
Whole blood samples of approximately 2 milliliters were collected for measurement of plasma concentrations of GSK2269557 at the indicated time points. The pharmacokinetic parameters were calculated by standard non-compartmental analysis. Pharmacokinetic (PK) Population which comprised of all randomized participants in the Safety Population and for whom a PK sample was obtained and analyzed.
Time frame: Day 1: Pre-dose, 5 minutes post dose, 30 minutes post-dose, 2 hours post-dose, 6 hours post-dose, 12 hours post-dose; Day 2: 24 hours post-dose; Day 3: 48 hours post-dose and Day 6: 120 hours post-dose
Area Under the Plasma Drug Concentration Versus Time Curve (AUC) From Zero to Time t (AUC [0 to t]), AUC From Zero to 24 Hours (AUC [0 to 24]) and AUC From Zero to Infinity (AUC [0 to Inf]) of GSK2269557
Blood samples were collected to evaluate the PK of GSK2269557 at the indicated time points. The PK parameters were calculated by standard non-compartmental analysis. Only those participants with data available at the specified time points were analyzed represented by n=X in the category titles.
Time frame: Day 1: Pre-dose, 5 minutes post dose, 30 minutes post-dose, 2 hours post-dose, 6 hours post-dose, 12 hours post-dose; Day 2: 24 hours post-dose; Day 3: 48 hours post-dose and Day 6: 120 hours post-dose
Maximum Observed Plasma Drug Concentration (Cmax) and Concentration at Trough (Ctrough) of GSK2269557
Blood samples were collected to evaluate the PK of GSK2269557 at the indicated time points. The PK parameters were calculated by standard non-compartmental analysis.
Time frame: Day 1: Pre-dose, 5 minutes post dose, 30 minutes post-dose, 2 hours post-dose, 6 hours post-dose, 12 hours post-dose; Day 2: 24 hours post-dose; Day 3: 48 hours post-dose and Day 6: 120 hours post-dose
Time to Maximum Observed Plasma Drug Concentration (Tmax) and Terminal Half-life (t1/2)
Blood samples were collected to evaluate the PK of GSK2269557 at the indicated time points. The PK parameters were calculated by standard non-compartmental analysis. Only those participants with data available at the specified time points were analyzed represented by n=X in the category titles.
Time frame: Day 1: Pre-dose, 5 minutes post dose, 30 minutes post-dose, 2 hours post-dose, 6 hours post-dose, 12 hours post-dose; Day 2: 24 hours post-dose; Day 3: 48 hours post-dose and Day 6: 120 hours post-dose
Number of Participants With Vital Signs of Potential Clinical Importance
Vital signs included blood pressure (systolic and diastolic blood pressure) and heart rate measurements and were assessed with the participant in a semi-supine position after 5 minutes rest. The potential clinical concern range values for vital signs were: systolic blood pressure (lower \<85 millimeters of mercury and higher \>160 millimeters of mercury), diastolic blood pressure (lower \<45 millimeters of mercury and higher \>100 millimeters of mercury) and heart rate (lower \<40 beats per minute and higher \>110 beats per minute). Number of participants with vital signs of potential clinical importance are presented. Safety Population comprised of all randomized participants who received at least one dose of study treatment.
Time frame: Up to Day 2
Number of Participants With Electrocardiogram (ECG) Values of Potential Clinical Importance
Twelve-lead ECG was obtained using an ECG machine which automatically measured PR, QRS, QT and corrected QT (QTc) intervals. ECG parameters and their potential clinical importance range values were: absolute QTc interval (lower \>450 milliseconds \[msec\]), absolute PR interval (lower \<110 msec and upper \>220 msec), absolute QRS interval (lower \<75 msec and upper \>110 msec). Number of participants with electrocardiogram (ECG) values of potential clinical importance are presented.
Time frame: Up to Day 2
Change From Baseline in Forced Vital Capacity (FVC) and Forced Expiratory Volume in 1 Second (FEV1)
The maximal amount of air forcefully exhaled in 1 second (FEV1) and forced vital capacity (FVC) was measured using a spirometer. Baseline was latest pre-dose assessment. Change from Baseline was calculated by subtracting Baseline values from post-dose visit values. Mean change from Baseline in FVC and FEV1 is presented.
Time frame: Baseline and Day 1
Number of Participants With Hematology Abnormalities of Potential Clinical Importance
Hematology parameters and their potential clinical concern values were: Hematocrit (high flag: \>0.54 and change from Baseline: decrease of 0.075), hemoglobin (high flag: \>180 grams per Liter and change from Baseline: decrease of 25 grams per Liter), lymphocytes (low flag: \<0.8\*10\^9 cells per Liter), neutrophil count (low flag: \<1.5\*10\^9 cells per Liter), platelet count (low flag: \<100\*10\^9 cells per Liter and high flag: \>550\*10\^9 cells per Liter) and white blood cell count (low flag: \<3\*10\^9 cells per Liter and high flag: \>20\*10\^9 cells per Liter). Number of participants with hematology abnormalities of potential clinical importance are presented.
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Time frame: Up to Day 2
Number of Participants With Clinical Chemistry Abnormalities of Potential Clinical Importance
Clinical chemistry parameters and their potential clinical concern range values were: calcium (low flag \<2 millimoles/Liter \[mmol/L\] and high flag \>2.75 mmol/L), creatinine (high flag \>44.2 micromoles/Liter increase in change from Baseline), glucose (fasting) (\<3 mmol/L and \>9 mmol/L), potassium (low flag \<3 mmol/L and high flag \>5.5 mmol/L above ULN), sodium (low flag \<130 mmol/L and high flag \>150 mmol/L). Number of participants with clinical chemistry abnormalities of potential clinical importance are presented.
Time frame: Up to Day 2
Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE)
AE is any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. For marketed medicinal products, this also includes failure to produce expected benefits (i.e., lack of efficacy), abuse or misuse. SAE is any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or is a congenital anomaly/birth defect or is medically significant.
Time frame: Up to 12 days post-dose