Infections, Bacterial
Conditions
Keywords
pharmacokinetics, GSK2140944, tolerability, drug interaction, safety, itraconazole, elderly healthy subjects, food effect, relative bioavailability
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.
Interventions
Immediate release capsule containing GSK2140944 and inactive formulation excipients with a unit dose strength of 500 mg
DRUGGSK2140944 tablet
Immediate release tablet containing GSK2140944 and inactive formulation excipients with a unit dose strength of 750 mg
Capsule containing Itraconazole with a unit dose strength of 100 mg
Sponsors
GlaxoSmithKline
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
Yes
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. * History of regular alcohol consumption within 6 months of the study defined as an average weekly intake of \>14 drinks for males or \>7 drinks for females. One drink is equivalent to 12 grams of alcohol: 12 ounces (360 mL) of beer, 5 ounces (150 mL) of wine or 1.5 ounces (45 mL) of 80 proof distilled spirits. * History of sensitivity to any of the study medications, or components thereof or a history of drug or other allergy that, in the opinion of the investigator or GSK Medical Monitor, contraindicates their participation. * History of sensitivity to heparin or heparin-induced thrombocytopenia (if the clinical research unit uses heparin to maintain intravenous cannula patency). Criteria Based Upon Diagnostic Assessments * A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of screening or positive Human Immunodeficiency Virus (HIV) antibody. * A screening or Day -1 urinalysis positive for protein or glucose (greater than 1+ findings of protein or glucose). * A serum creatinine value that is increased by more than 0.2 milligram (mg)/deciliter (dL) (or 15.25 micromoles/L) between screening and Day -1. * For Part 3 Only: Neutrophil count \<2000 cells/microliter (a single repeat is allowed for eligibility determination). * A positive urine test for drugs of abuse or alcohol (or alcohol breath test) at screening or at Day -1. *
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part 1: Composite of PK parameters following GSK2140944 administration in fasted and fed state | 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 2: Composite of PK parameters of GSK2140944 following repeat oral dosing of itraconazole | 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. |
| Part 3: Safety and tolerability of GSK2140944 as assessed by adverse events (AEs) | Approximately 8 weeks | — |
| Part 3: Safety and tolerability of GSK2140944 as assessed by review of concomitant medications | Approximately 8 weeks | — |
| Part 3: Safety and tolerability of GSK2140944 by laboratory assessments | 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) | 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 | 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Part 2: Safety and tolerability of GSK2140944 as assessed by 12-lead ECGs | Approximately 6 weeks | All 12-lead ECGs will be obtained after the subject has rested in a supine position for at least 10 minutes |
| Part 1: Safety and tolerability of GSK2140944 as assessed by AEs | Approximately 7 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) | PK parameters will include AUC over the dosing interval (0-tau), tmax, tlag, t1/2, pre-dose (trough) concentration at the end of the dosing interval (Ctau) and Cmax of GSK2140944 |
| Part 2: Safety and tolerability of GSK2140944 as assessed by vital signs | Approximately 6 weeks | Vital signs will be measured for subjects in supine position and will include systolic and diastolic blood pressure, pulse rate and temperature |
| Part 1: Safety and tolerability of GSK2140944 as assessed by review of concomitant medications | Approximately 7 weeks | — |
| Part 1: Safety and tolerability of GSK2140944 by laboratory assessments | Approximately 7 weeks | Laboratory assessments will include hematology, clinical chemistry, urinalysis parameters |
| Part 1: Safety and tolerability of GSK2140944 as assessed by 12-lead ECGs | Approximately 7 weeks | All 12-lead ECGs will be obtained after the subject has rested in a supine position for at least 10 minutes |
| Part 1: Safety and tolerability of GSK2140944 as assessed by vital signs | Approximately 7 weeks | Vital signs will be measured for subjects in supine position and will include systolic and diastolic blood pressure, pulse rate and temperature |
| Part 2: Safety and tolerability of GSK2140944 as assessed by AEs | Approximately 6 weeks | — |
| Part 2: Safety and tolerability of GSK2140944 by laboratory assessments | Approximately 6 weeks | Laboratory assessments will include hematology, clinical chemistry, urinalysis parameters |
Countries
United States
Outcome results
None listed