A Single-Center, Three-Part, Open Label Study to Evaluate the Relative Bioavailability of Two Formulations, Food Effect, and Interaction With Itraconazole Following Single Dose of GSK2140944 in Healthy Subjects and Effect of Food on Safety, Tolerability, and Pharmacokinetics Following Multiple Doses of GSK2140944 in Healthy Elderly Subjects
Overview
- Phase
- Phase 1
- Intervention
- GSK2140944 capsule
- Conditions
- Infections, Bacterial
- Sponsor
- GlaxoSmithKline
- Enrollment
- 46
- Locations
- 1
- Primary Endpoint
- Part 1: Composite of PK parameters following GSK2140944 administration in fasted and fed state
- Status
- Completed
- Last Updated
- 8 years ago
Overview
Brief Summary
This study will be conducted in three parts (Part 1, Part 2 and Part 3). Part 1 of this study will evaluate the relative bioavailability of a single dose of GSK2140944 tablet formulation compared to the reference capsule formulation under fasted conditions. The effect of food on the pharmacokinetics (PK) of a single dose of the tablet formulation will also be assessed. Part 2 will evaluate the effect of repeat doses of itraconazole on the pharmacokinetics of GSK2140944 following a single dose. A decision will be made whether to use the current capsule formulation or the new tablet formulation in Part 2 based upon the safety and PK data obtained from Part 1. Part 3 is conditionally based upon progression of the tablet formulation from Part 1 and will evaluate the effect of food on the safety, tolerability, and pharmacokinetics of the tablet formulation following multiple doses in elderly healthy subjects.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Healthy as determined by a responsible and experienced physician, based on a medical evaluation including medical history, physical examination, laboratory tests and cardiac monitoring. A subject with a clinical abnormality or laboratory parameters outside the reference range for the population being studied may be included only if the Investigator feels and documents that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures.
- •Part 1 and 2: Male or female between 18 and 64 years of age inclusive, at the time of signing the informed consent. Part 3: Male or female subjects at least 65 years of age or older at the time of signing the informed consent.
- •A female subject is eligible to participate if she is of: non-childbearing potential defined as pre-menopausal females with a documented tubal ligation or hysterectomy; or postmenopausal defined as 12 months of spontaneous amenorrhea. To confirm post-menopausal status, a blood sample for simultaneous follicle stimulating hormone (FSH) \>40 milli-International Units (MIU)/milliliter (mL) and estradiol \<40 picograms (pg)/mL (\<147 picomoles \[pmol\]/liter \[L\]) is confirmatory. Male subjects with female partners of child-bearing potential must agree to use one of the contraception methods. This criterion must be followed from the time of the first dose of study medication until the final follow-up visit.
- •Body weight \>=50 kilograms (kg) and body mass index (BMI) within the range 19 - 31 kg/meter square (m\^2) (inclusive).
- •Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.
- •Alanine amino transferase (ALT), alkaline phosphatase and bilirubin \<=1.5xUpper Limit of Normal (ULN) (isolated bilirubin \>1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin \<35%).
Exclusion Criteria
- •Criteria Based Upon Medical Histories
- •Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
- •Any clinically significant central nervous system (e.g., seizures), cardiac, pulmonary, metabolic, renal, hepatic or gastrointestinal conditions or history of such conditions that, in the opinion of the investigator may place the subject at an unacceptable risk as a participant in this trial or may interfere with the absorption, distribution, metabolism or excretion of drugs.
- •History of photosensitivity to quinolones.
- •Use of systemic antibiotic within 30 days of screening
- •Previous exposure to GSK2140944
- •Confirmed history of C-difficile diarrhea.
- •History of tendon rupture.
- •History of drug abuse within 6 months of the study.
- •History of smoking or use of nicotine containing products within 3 months of screening, or a positive urine cotinine indicative of smoking at screening.
Arms & Interventions
Part 1
Subjects will receive either GSK2140944 1500 mg (500 mg x 3) capsules under fasted conditions or GSK2140944 1500 mg (750 mg x 2) tablets under fasted conditions or GSK2140944 1500 mg (750 mg x 2) tablets under fed conditions as per the randomization schedule in each of the three periods with a washout period of at least 3 days between the doses. There will also be a follow-up visit within 5-7 days after the last dose of study drug.
Intervention: GSK2140944 capsule
Part 1
Subjects will receive either GSK2140944 1500 mg (500 mg x 3) capsules under fasted conditions or GSK2140944 1500 mg (750 mg x 2) tablets under fasted conditions or GSK2140944 1500 mg (750 mg x 2) tablets under fed conditions as per the randomization schedule in each of the three periods with a washout period of at least 3 days between the doses. There will also be a follow-up visit within 5-7 days after the last dose of study drug.
Intervention: GSK2140944 tablet
Part 2
Subjects will receive a single dose of GSK2140944 1500 mg (tablet or capsule) on Day 1 followed by a repeat dose of Itraconazole 200 mg once daily for 6 days from Day 4 to Day 9. On Day 7, subjects will receive a single dose of GSK2140944 1500 mg (tablet or capsule) one hour after the dose of Itraconazole. There will also be a follow-up visit within 5-7 days after the last dose of study drug.
Intervention: GSK2140944 capsule
Part 2
Subjects will receive a single dose of GSK2140944 1500 mg (tablet or capsule) on Day 1 followed by a repeat dose of Itraconazole 200 mg once daily for 6 days from Day 4 to Day 9. On Day 7, subjects will receive a single dose of GSK2140944 1500 mg (tablet or capsule) one hour after the dose of Itraconazole. There will also be a follow-up visit within 5-7 days after the last dose of study drug.
Intervention: GSK2140944 tablet
Part 2
Subjects will receive a single dose of GSK2140944 1500 mg (tablet or capsule) on Day 1 followed by a repeat dose of Itraconazole 200 mg once daily for 6 days from Day 4 to Day 9. On Day 7, subjects will receive a single dose of GSK2140944 1500 mg (tablet or capsule) one hour after the dose of Itraconazole. There will also be a follow-up visit within 5-7 days after the last dose of study drug.
Intervention: Itraconazole capsule
Part 3
Subjects in Group 1 will receive GSK2140944 1500 mg (750 mg x 2) tablets twice daily from Day 1 to Day 5 under fasting and fed conditions in Period I and Period II, respectively. Subjects in Group 2 will receive GSK2140944 1500 mg (750 mg x 2) tablets twice daily from Day 1 to Day 5 under fed and fasting conditions in Period I and Period II, respectively. There will be a washout of at least 7 days between the periods. Subjects will have a follow up visit 5-7 days after the last dose of study drug in both the groups.
Intervention: GSK2140944 tablet
Outcomes
Primary Outcomes
Part 1: Composite of PK parameters following GSK2140944 administration in fasted and fed state
Time Frame: Day 1 (Pre-dose, 0.25h, 0.5h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 12h, 24h, 36h, and at 48h)
PK parameters will include area under the concentration-time curve (AUC) from time zero (pre-dose) extrapolated to infinite time AUC(0-infinity), AUC from time zero to last quantifiable concentration AUC(0-t), relative bioavailability of drug (Frel), maximum observed concentration (Cmax), time of occurrence of Cmax (tmax), lag time before observation of drug concentration (tlag) and terminal phase half-life (t1/2) in the fasted state; AUC(0-infinity), AUC(0-t), tmax, tlag and Cmax after moderate fat meal.
Part 3: Safety and tolerability of GSK2140944 as assessed by review of concomitant medications
Time Frame: Approximately 8 weeks
Part 3: Safety and tolerability of GSK2140944 by laboratory assessments
Time Frame: Approximately 8 weeks
Laboratory assessments will include hematology, clinical chemistry, urinalysis parameters
Part 3: Safety and tolerability of GSK2140944 as assessed by 12-lead electrocardiograms (ECGs)
Time Frame: Approximately 8 weeks
All 12-lead ECGs will be obtained after the subject has rested in a supine position for at least 10 minutes
Part 3: Safety and tolerability of GSK2140944 as assessed by vital signs
Time Frame: Approximately 8 weeks
Vital signs will be measured for subjects in supine position and will include systolic and diastolic blood pressure, pulse rate and temperature
Part 3: Safety and tolerability of GSK2140944 as assessed by adverse events (AEs)
Time Frame: Approximately 8 weeks
Part 2: Composite of PK parameters of GSK2140944 following repeat oral dosing of itraconazole
Time Frame: Day 1 and Day 7 (Predose, 0.25h, 0.5h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 12h, 24h, 36h, and 48h post dose and also at 60h and 72h post dose on Day 7
PK parameters will include AUC(0-infinity), AUC(0-t), tmax, tlag and Cmax of GSK2140944.
Secondary Outcomes
- Part 2: Safety and tolerability of GSK2140944 as assessed by AEs(Approximately 6 weeks)
- Part 1: Safety and tolerability of GSK2140944 as assessed by AEs(Approximately 7 weeks)
- Part 1: Safety and tolerability of GSK2140944 by laboratory assessments(Approximately 7 weeks)
- Part 1: Safety and tolerability of GSK2140944 as assessed by 12-lead ECGs(Approximately 7 weeks)
- Part 1: Safety and tolerability of GSK2140944 as assessed by vital signs(Approximately 7 weeks)
- Part 2: Safety and tolerability of GSK2140944 as assessed by 12-lead ECGs(Approximately 6 weeks)
- Part 2: Safety and tolerability of GSK2140944 by laboratory assessments(Approximately 6 weeks)
- Part 2: Safety and tolerability of GSK2140944 as assessed by vital signs(Approximately 6 weeks)
- Part 3: Composite of PK parameters of GSK2140944 following repeat oral dosing of GSK2140944(Day 3 and Day 4 (Pre-dose), Day 5 (Predose, 0.25h, 0.5h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 12h, 24h, 36h, and at 48h))
- Part 1: Safety and tolerability of GSK2140944 as assessed by review of concomitant medications(Approximately 7 weeks)