Drug Interactions, Neoplasms
Conditions
Keywords
Itraconazole, Rifampicin, Pharmacokinetics, Cross-over
Brief summary
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.
Interventions
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
DRUGRifampicin 300 mg
Rifampicin is available as a red capsule with printed markings and as a 300 mg unit dose strength.
Sponsors
GlaxoSmithKline
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 70 Years
Healthy volunteers
Yes
Inclusion criteria
* Between 18 and 70 years of age inclusive, at the time of signing the informed consent. * Healthy as determined by the investigator or medically qualified designee based on a medical evaluation including medical history, physical examination, and laboratory tests. * A subject with a clinical abnormality or laboratory parameter(s) which is/are not specifically listed in the inclusion or
Exclusion criteria
, outside the reference range for the population being studied may be included only if the investigator in consultation with the Medical Monitor agree and document that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures. * Body Weight \>=45 Kilograms (Kg) and body mass index within the range 18.0 - 29.9 Kilograms/squared meter (kg/m\^2) (inclusive) at time of screening. * Only female subjects of non child bearing potential are eligible for screening; men are not eligible for this study. Female subjects: are eligible to participate if she is not pregnant (as confirmed by a negative serum human chorionic gonadotrophin (hCG) test at screening and serum or urine hCG prior to dosing), is not lactating, and lacks reproductive potential, defined as: * Pre-menopausal females with one of the following: 1. Documented tubal ligation 2. Documented hysteroscopic tubal occlusion procedure with follow-up confirmation of bilateral tubal occlusion 3. Hysterectomy 4. Documented Bilateral Oophorectomy * Postmenopausal defined as 12 months of spontaneous amenorrhea \[in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) and estradiol levels consistent with menopause (refer to laboratory reference ranges for confirmatory levels)\]. * Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the consent form and in this protocol.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| 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 | 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 | 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 | 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 | 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 | 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 | 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Part 1: Heart rate assessment as a safety measure. | Up to 45 days | Heart rate will be measured on each day in supine or semi-supine position after 5 minutes rest. |
| Part 2: Number of subjects with adverse event (AE) and serious adverse event (SAE) | Up to 56 days | 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. |
| Part 2: Number of subjects having abnormal haematology parameters as a measure of safety. | Up to 56 days | 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). |
| Part 2: Number of subjects having abnormal clinical chemistry parameters as a measure of safety. | Up to 56 days | 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 |
| Part 1: Number of subjects with adverse event (AE) and serious adverse event (SAE) | Up to 45 days | 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 |
| Part 2: ECG assessment as a measure of safety and tolerability. | Up to 56 days | 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. |
| Part 2: Blood pressure assessment as a safety measure. | Up to 56 days | Systolic and diastolic blood pressure will be measured on each day in supine or semi-supine position after 5 minutes rest. |
| Part 2: Heart rate assessment as a safety measure. | Up to 56 days | Heart rate will be measured on each day in supine or semi-supine position after 5 minutes rest. |
| Part 2: Number of subjects having abnormal urine parameters (using dipstick test) as a measure of safety. | Up to 56 days | 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. |
| Part 1: Number of subjects having abnormal haematology parameters as a measure of safety. | Up to 45 days | 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). |
| Part 1: Number of subjects having abnormal clinical chemistry parameters as a measure of safety | Up to 45 days | 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 |
| Part 1: Number of subjects having abnormal urine parameters (using dipstick test) as a measure of safety | Up to 45 days | 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. |
| Part 1: Electrocardiogram (ECG) assessment as a measure of safety and tolerability | Up to 45 days | 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. |
| Part 1: Blood pressure assessment as a safety measure. | Up to 45 days | Systolic and diastolic blood pressure will be measured on each day in supine or semi-supine position after 5 minutes rest. |
Countries
United States
Outcome results
None listed