GSK2894512 (trans-isomer) is a fully synthetic, non-steroidal anti-inflammatory agent. This study is being conducted to evaluate the PK, safety and tolerability of GSK2894512 cream, 1 percent administered topically to healthy adult subjects. PK parameters obtained in this study will be used to support the design of future maximum use PK (MUPK) studies in subjects with atopic dermatitis (AD) and plaque psoriasis or psoriasis (PSO). This is a phase 1, randomized, double-blind, vehicle-controlled, 3-period, sequential, inpatient study consists of a Screening visit, 3 treatment periods and a follow-up visit. GSK2894512 cream, 1 percent (or matching vehicle) will be administered sequentially in the treatment periods. Period 1 will include once daily repeated topical applications on approximately 5000 centimeter (cm) \^2 intact non-occluded skin area for 21 days. Period 2 will include once daily repeated topical applications on approximately 5000 cm\^2 intact occluded skin area for 21 days. Period 3 will include a single topical application on up to 400 cm\^2 gently taped-stripped skin area. Each treatment regimen will be followed by washout period for approximately 21 days, except for Treatment Period 3. Approximately 26 healthy adult subjects will be enrolled in to the study. Total duration of participation in this study will be approximately 18 weeks.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
DOUBLE
It will be prepared as close as possible to the time of administration to avoid a prolonged exposure to light. Each single cream application will be made by weight, dispensed on hand (fingertips) covered with clean disposable glove and evenly spread using fingertips.
It will be prepared as close as possible to the time of administration to avoid a prolonged exposure to light. Each single cream application will be made by weight, dispensed on hand (fingertips) covered with clean disposable glove and evenly spread using fingertips.
Plasma concentrations of GSK2894512 (trans-isomer)
Blood samples will be collected at the indicated time points to evaluate plasma concentration of GSK2894512 (trans-isomer).
Time frame: Days 1, 7, 14, 21: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 16 hours; Days 2, 3, 8, 9, 15, 16, 22, 23: Pre-dose, in Period-1 and 2. Period-3: Day 1: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 16, 24, 48 hours
Area under the plasma concentration-time curve from time zero to the end of the dosing interval (AUC [0-tau]) of GSK2894512
Blood sample will be collected at the indicated time points to evaluate PK profile of GSK2894512.
Time frame: Days 1, 7, 14, 21: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 16 hours; Days 2, 3, 8, 9, 15, 16, 22, 23: Pre-dose, in Period-1 and 2. Period-3: Day 1: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 16, 24, 48 hours
Area under the plasma concentration-time curve from time zero to the last measurable concentration (AUC [0-t) of GSK2894512
Blood sample will be collected at the indicated time points to evaluate PK profile of GSK2894512.
Time frame: Days 1, 7, 14, 21: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 16 hours; Days 2, 3, 8, 9, 15, 16, 22, 23: Pre-dose, in Period-1 and 2. Period-3: Day 1: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 16, 24, 48 hours
Maximum observed serum concentration (Cmax) of GSK2894512
Blood sample will be collected at the indicated time points to evaluate PK profile of GSK2894512.
Time frame: Days 1, 7, 14, 21: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 16 hours; Days 2, 3, 8, 9, 15, 16, 22, 23: Pre-dose, in Period-1 and 2. Period-3: Day 1: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 16, 24, 48 hours
Time of maximum concentration observed (tmax) of GSK2894512
Blood sample will be collected at the indicated time points to evaluate PK profile of GSK2894512.
Time frame: Days 1, 7, 14, 21: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 16 hours; Days 2, 3, 8, 9, 15, 16, 22, 23: Pre-dose, in Period-1 and 2. Period-3: Day 1: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 16, 24, 48 hours
Apparent terminal phase half life (t1/2) of GSK2894512
Blood sample will be collected at the indicated time points to evaluate PK profile of GSK2894512.
Time frame: Days 1, 7, 14, 21: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 16 hours; Days 2, 3, 8, 9, 15, 16, 22, 23: Pre-dose, in Period-1 and 2. Period-3: Day 1: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 16, 24, 48 hours
Trough concentration at the end of the dosing interval (Ctau) of GSK2894512
Blood sample will be collected at the indicated time points to evaluate PK profile of GSK2894512.
Time frame: Days 1, 7, 14, 21: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 16 hours; Days 2, 3, 8, 9, 15, 16, 22, 23: Pre-dose, in Period-1 and 2. Period-3: Day 1: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 16, 24, 48 hours
Accumulation ratio (Ro) of GSK2894512
Blood sample will be collected at the indicated time points to evaluate PK profile of GSK2894512.
Time frame: Days 1, 7, 14, 21: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 16 hours; Days 2, 3, 8, 9, 15, 16, 22, 23: Pre-dose, in Period-1 and 2. Period-3: Day 1: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 16, 24, 48 hours
Number of subjects with any adverse events (AEs) and serious AEs (SAEs)
An AE is any untoward medical occurrence in a clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An SAE is defined as any untoward medical occurrence that: results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, other important medical events judged by physician that may not be immediately life-threatening or result in death or hospitalization but may jeopardize the subject or may require medical or surgical intervention to prevent one of the other outcomes listed in this definition.
Time frame: Up to 14 weeks
Number of subjects with abnormal vital sign findings
Vital sign parameters including systolic and diastolic blood pressure, heart rate (HR) and body temperature will be evaluated. Vital sign measurements will be preceded by at least 5 minutes of rest (supine or seated) for the subject in a quiet setting.
Time frame: Up to 13 weeks
Number of subjects with abnormal electrocardiogram (ECG) findings
Triplicate 12-lead ECG will be obtained using an ECG machine that automatically calculates the HR and measures PR, QRS, QT, and QT interval corrected for heart rate according to Fridericia's formula (QTcF) intervals on Days -1, 3, 9, 16 and 23 in Period-1 and 2; and on Days -1 and 3 in Period-3.
Time frame: Up to 13 weeks
Number of subjects with abnormal findings in digital holter monitoring
Continuous digital 12-lead ECGs will be recorded using 12-lead Holter/12-lead ECG recorder from 1 hour prior to dosing to 24 hours after dosing on Days 1, 2, 7, 8, 14, 15, 21 and 22 in period-1 and 2; and on Days 1 and 2 in Period-3.
Time frame: Up to 13 weeks
Number of subjects with abnormal findings in physical examination
Complete physical examination will include review of head and neck, heart, lungs, abdomen, skin, general appearance, height and weight.
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Time frame: Up to 13 weeks
Number of subjects with abnormal clinical laboratory findings
Serum chemistry, hematological and urine analysis parameters will be evaluated.
Time frame: Up to 13 weeks
Assessment of degree of local irritation as a measure of local tolerability
Dermal reactions like erythema, edema, papules at test sites will be visually assessed. Degree of local irritation will be assessed to determine tolerability of topical application of GSK2894512 cream. if a subject is found to meet a dermal response graded 4 (definite edema) and above indicated in Erythema and Dermal Response Grading Scale, the study medication applications will be discontinued. Grade \<4 will be recorded as an AE.
Time frame: Up to 14 weeks