This is a Phase I, single center, two-part, randomized, open label, cross-over study. Part 1 of this study will evaluate the PK, safety, and tolerability of GSK525762 when administered alone and when co-administered following repeat dosing of itraconazole, a known strong inhibitor of Cytochrome P450 3A4 (CYP3A4) and a Para-glycoprotein (Pgp) inhibitor. Part 1 will consist of 2 Cohorts with preliminary PK and safety data obtained from Cohort 1 informing Cohort 2. Part 2 (one Cohort) of the study will evaluate the PK, safety, and tolerability of GSK525762 when administered alone and when co-administered following repeat dosing of rifampicin, a known potent inducer of CYP3A4. In vitro inhibition data indicate CYP3A4 may be the major route of clearance for GSK525762 and co-administration of drug therapies which modulate CYP3A4 (i.e.CYP3A4 inhibitors and inducers) is likely to alter the exposure of GSK525762 (i.e. increase or decrease exposure, respectively). The data generated from this current study to justify exclusion criteria on concomitant medications which affect CYP3A4 or Pgp and also inform potential dose modification in case of co-administration with medication affecting CYP3A4 activity. All subjects will undergo a screening visit within 28 days of the first dose of study drug followed by one treatment period and a follow-up visit 7-10 days after the last dose of GSK525762. Subjects in Part 1 will participate in the study for up to 45 days and subjects in Part 2 will participate for up to 56 days.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
29
GSK525762 is available as a film-coated, white to slightly colored round, biconvex tablets with no markings. It is available in unit dose strength of 5 mg.
Itraconazole is available as a clear yellow solution with unit dose strength of 10 mg/mL
Rifampicin is available as a red capsule with printed markings and as a 300 mg unit dose strength.
GSK Investigational Site
Baltimore, Maryland, United States
Part 1: Area under the plasma concentration-time curve (AUC) from pre dose to time 't' (AUC[0-t]) and pre dose to infinite time (AUC[0-infinity]) of GSK525762 and metabolites in the presence and absence of itraconazole
Time frame: Day 1: Pre dose, 15 min, 30 min, 1 hr, 1.5 hr, 2 hr, 3 hr, 4 hr, 8 hr, 12 hr, 24 hr , 36 hr, and 48 hr post dose. Day 7:Pre dose, 15 min, 30 min, 1 hr, 1.5 hr, 2 hr, 3 hr, 4 hr, 8 hr, 12 hr, 24 hr, 36 hr, 48 hr and 72 hr.
Part 1: Maximum plasma concentration (Cmax) of GSK525762 and metabolites in the presence and absence of itraconazole
Time frame: Day1 (Pre dose and 15 min, 30 min, 1 hr, 1.5 hr, 2 hr, 3 hr, 4 hr, 8 hr, 12 hr, 24 hr, 36 hr, and 48 hr post dose) and Day7 (Pre dose and 15 min, 30 min, 1 hr, 1.5 hr, 2 hr, 3 hr, 4 hr, 8 hr, 12 hr, 24 hr, 36 hr, 48 hr and 72 hr post dose) of each cohort
Part 1: Time to maximum plasma concentration (tmax) of GSK525762 and metabolites in the presence and absence of itraconazole
Time frame: Day1 (Pre dose, 15 min, 30 min, 1 hr, 1.5 hr, 2 hr, 3 hr, 4 hr, 8 hr, 12 hr, 24 hr , 36 hr, and 48 hr) and Day7 (Pre dose, 15 min, 30 min, 1 hr, 1.5 hr, 2 hr, 3 hr, 4 hr, 8 hr, 12 hr, 24 hr, 36 hr, 48 hr and 72 hr) of each cohort
Part 2: (AUC[0-t]) and (AUC[0-infinity]) of GSK525762 and metabolites in the presence and absence of rifampicin
Time frame: Blood samples will be collected on Day1 and Day 18 at Pre dose, 15 min, 30 min, 1 hr, 1.5 hr, 2 hr, 3 hr, 4 hr, 8 hr, 12 hr, 24 hr (Day 19), 36 hr, and 48 hr (Day 20) post dose
Part 2: Cmax of GSK525762 and metabolites in the presence and absence of rifampicin
Time frame: Blood samples will be collected on Day 1 and Day 18 at Pre dose, 15 min, 30 min, 1 hr, 1.5 hr, 2 hr, 3 hr, 4 hr, 8 hr, 12 hr, 24 hr (Day 19), 36 hr, and 48 hr (Day 20) post dose
Part 2: tmax of GSK525762 and metabolites in the presence and absence of rifampicin
Time frame: Blood samples will be collected on Day 1 and Day 18 at Pre dose, 15 min, 30 min, 1 hr, 1.5 hr, 2 hr, 3 hr, 4 hr, 8 hr, 12 hr, 24 hr (Day 19), 36 hr, and 48 hr (Day 20) post dose
Part 1: Number of subjects with adverse event (AE) and serious adverse event (SAE)
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. Any untoward event resulting in death, life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, congenital anomaly/birth defect or any other situation according to medical or scientific judgement will be categorized as SAE
Time frame: Up to 45 days
Part 1: Number of subjects having abnormal haematology parameters as a measure of safety.
Blood samples will be collected at screening, pre dose (Day 1), and post dose on Day 3,Day 6 and at follow-up visit to analyze platelet counts, red blood cells (RBC) count, white blood cells (WBC) count (absolute), haemoglobin, hematocrit and differential WBC count ( neutrophils, lymphocytes, monocytes, eosinophils, and basophils).
Time frame: Up to 45 days
Part 1: Number of subjects having abnormal clinical chemistry parameters as a measure of safety
Blood samples will be collected at screening, pre dose (Day 1), and post dose on Day 3,Day 6 and at follow-up visit to analyze blood urea nitrogen (BUN), creatinine, glucose (fasting), sodium, c peptide, potassium, chloride, magnesium, ionized calcium, aspartate aminotransferase (AST/SGOT), alanine aminotransferase (ALT/SGPT), alkaline phosphatase (ALP) levels, gamma-glutamyltransferase (GGT), total and direct bilirubin, total carbon dioxide, total protein and albumin
Time frame: Up to 45 days
Part 1: Number of subjects having abnormal urine parameters (using dipstick test) as a measure of safety
Urine samples will be collected at screening, pre dose (Day 1), and post dose on Day 3,Day 6 and at follow-up visit to analyze specific gravity, pH, glucose, protein, blood and ketone bodies by dipstick method, microscopic examination (if blood or protein is abnormal) WBCs, RBCs, hyaline casts, granular casts and cellular casts.
Time frame: Up to 45 days
Part 1: Electrocardiogram (ECG) assessment as a measure of safety and tolerability
This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.
ECGs will be measured in supine position after 5 minutes rest using a standard 12-lead ECG machine that automatically calculates the HR and measures PR, QRS, QT and QTcF intervals.
Time frame: Up to 45 days
Part 1: Blood pressure assessment as a safety measure.
Systolic and diastolic blood pressure will be measured on each day in supine or semi-supine position after 5 minutes rest.
Time frame: Up to 45 days
Part 1: Heart rate assessment as a safety measure.
Heart rate will be measured on each day in supine or semi-supine position after 5 minutes rest.
Time frame: Up to 45 days
Part 2: Number of subjects with adverse event (AE) and serious adverse event (SAE)
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. Any untoward event resulting in death, life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, congenital anomaly/birth defect or any other situation according to medical or scientific judgement will be categorized as SAE.
Time frame: Up to 56 days
Part 2: Number of subjects having abnormal haematology parameters as a measure of safety.
Blood samples will be collected at screening, pre dose (Day 1), and post dose on Day 3,Day 4, Day 17 and at follow-up to analyze platelet counts, RBC count, WBC count (absolute), haemoglobin, hematocrit and differential WBC count ( neutrophils, lymphocytes, monocytes, eosinophils, and basophils).
Time frame: Up to 56 days
Part 2: Number of subjects having abnormal clinical chemistry parameters as a measure of safety.
Blood samples will be collected at screening, pre dose (Day 1), and post dose on Day 3,Day 4, Day 17 and at follow-up visit to analyze BUN, creatinine, glucose (fasting), sodium, c peptide, potassium, chloride, magnesium, ionized calcium, AST/SGOT, ALT/SGPT, ALP levels, GGT, total and direct bilirubin, total carbon dioxide, total protein and albumin
Time frame: Up to 56 days
Part 2: Number of subjects having abnormal urine parameters (using dipstick test) as a measure of safety.
Urine samples will be collected at screening, pre dose (Day 1), and post dose on Day 3,Day 4, Day 17 and at follow-up visit to analyze specific gravity, pH, glucose, protein, blood and ketone bodies by dipstick method, microscopic examination (if blood or protein is abnormal) WBCs, RBCs, hyaline casts, granular casts and cellular casts.
Time frame: Up to 56 days
Part 2: ECG assessment as a measure of safety and tolerability.
On Day 1 and Day 18 ECGs will be measured in supine position after 5 minutes rest at screening, pre-dose, 1 hr, 24 hr and 48 hrs.
Time frame: Up to 56 days
Part 2: Blood pressure assessment as a safety measure.
Systolic and diastolic blood pressure will be measured on each day in supine or semi-supine position after 5 minutes rest.
Time frame: Up to 56 days
Part 2: Heart rate assessment as a safety measure.
Heart rate will be measured on each day in supine or semi-supine position after 5 minutes rest.
Time frame: Up to 56 days