This Study Will Investigate the Safety, Tolerability and Pharmacokinetic Profile of Repeat Oral Doses of GSK2140944 in Healthy Adult Subjects

This will be a randomized, placebo-controlled, single blind study to investigate the safety, tolerability and pharmacokinetic (PK) profile of GSK2140944 following repeat oral doses in healthy adult subjects. The study will include a Screening period (40 days), Treatment period (16 days) and a Follow-up period (26 to 30 days). A single dose will be administered on Day 1 for characterization of single dose PK, followed by twice-daily (BID) or thrice-daily (TID) dosing on Days 3 to 16. Subjects may only be randomized to one cohort per the randomization schedule. Up to 6 cohorts will be enrolled using a sequential panel. Subjects in Cohort 1 will receive GSK2140944 (6) and placebo (2). Subsequent cohorts will enroll 16 subjects such that 12 subjects will receive GSK2140944 and 4 subjects will receive placebo, per dose level according to the randomization schedule. Dose escalations are planned to run in successive weeks. Cohort 2 may begin dosing once subjects in Cohort 1 have completed 7 days of BID dosing, PK data is reviewed and safety data from at least 6 subjects is available. Each subsequent dose escalation will commence only when GSK2140944 safety data and available PK data of at least 12 subjects dosed at the previous dose level have been reviewed. The number of cohorts may be reduced or expanded if needed. The first planned dose is 400 milligram (mg) BID but may be modified based upon emergent PK, safety and tolerability data from ongoing clinical study BTZ115198 evaluating single and repeat intravenous (IV) doses of GSK2140944. The projected dose for Cohort 2 is 800 mg BID, Cohort 3 is 1500 mg BID, Cohort 4 is 2300 mg BID or 1500 mg TID and Cohort 5 and cohort 6 will be decided later. The planned maximum dose is 2500 mg TID but may be modified based upon emergent safety, tolerability and PK data. Doses of GSK2140944 or placebo will be administered following a moderate fat meal.


Eligibility Criteria:
Inclusion Criteria:

* Aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase and bilirubin \<=1.5x upper limit of normal (ULN) (isolated bilirubin \>1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin \<35%).
* 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 and the GlaxSmithKline (GSK) Medical Monitor agree that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures.
* Male or female between 18 and 60 years of age inclusive, 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 MlU/ml and estradiol \<40 pg/ml (\<147 pmol/L) is confirmatory. Male subjects with female partners of child-bearing potential must agree to use 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 kg and body mass index (BMI) within the range 19 to 31 kg/m2 (inclusive).
* Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.

Exclusion Criteria:

* 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.
* Current or chronic history of liver disease, or known hepatic or biliary abnormalities.
* 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.
* A screening or Day -2 urinalysis positive for protein or glucose (greater than "trace" findings of protein or glucose).
* A serum creatinine value between screening and Day -2 visit that is increased by more than 0.2 mg/dL (or 15.25 umol/L) changes.
* History of photosensitivity to quinolones and tendon rupture.
* Unwillingness to commit to avoid excessive exposure to sunlight which would cause a sunburn reaction from first dose up to and including the follow-up visit.
* A positive urine test for drugs of abuse or alcohol (or alcohol breath test) at screening or Day -2.
* 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 g 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.
* The subject has participated in a clinical trial and has received a drug or a new chemical entity within 30 days or 5 half-lives, or twice the duration of the biological effect of any drug (whichever is longer) prior to the first dose of current study medication.
* Use of prescription or non-prescription drugs, including vitamins, herbal and dietary supplements within 7 days or 5 half-lives (whichever is longer) prior to the first dose of study medication, or use of St. John's Wort within 14 days prior to the first dose of study medication. By exception, the volunteer may take paracetamol or acetaminophen (\<=2 grams/day) up to 48 hours prior to the first dose of study medication. However, the Investigator and GSK study team can review medication on a case by case basis to determine if its use would compromise subject safety or interfere with the study procedures or data interpretation.
* 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).
* Donation of blood in excess of 500 ml within 12 weeks prior to dosing.
* Consumption of red wine, seville oranges, grapefruit or grapefruit juice, pummelos, exotic citrus fruits, grapefruit hybrids or fruit juices containing such products from 7 days prior to the first dose of study medication.
* Screening ECG: Heart rate \<40 and \>100 bpm for males and \<50 and \>100 bpm for females. PR Interval \<120 and \>220 msec, QRS duration \<70 and \>100 msec, QTcB or QTcF interval \>450msec. Evidence of previous myocardial infarction (does not include ST segment changes associated with repolarization); any conduction abnormality (including but not specific to left or right complete bundle branch block, atrioventricular (AV) block \[2nd degree or higher\], Wolf Parkinson White \[WPW\] syndrome), sinus pauses \>3 seconds, non-sustained or sustained ventricular tachycardia (\>=3 consecutive ventricular ectopic beats) or any significant arrhythmia which, in the opinion of the principal investigator and GSK medical monitor, will interfere with the safety of the individual subject.
* Screening holter monitoring shows one or more of the following: any symptomatic arrhythmia (except isolated extra systoles); sustained cardiac arrhythmias (such as atrial fibrillation or flutter, supraventricular tachycardia (SVT) \[\>10 consecutive beats\]); sinus tachycardia (or SVT) \>150 bpm; non-sustained or sustained ventricular tachycardia (defined as \>=3 consecutive ventricular ectopic beats); any conduction abnormality (including but not specific to left or right complete bundle branch block, AV block \[2nd degree or higher in an awake subject\], WPW syndrome, other pre-excitation syndromes); symptomatic sinus pause or sinus pause \>3 seconds - unless patient is straining, vomiting, or having some other type of hypervagal response; 300 or more supraventricular ectopic beats in 24 hours; 250 or more ventricular ectopic beats in 24 hours; Ischemia, diagnosed by a sequence of EKG changes that include flat or down sloping ST-segment depression \>0.1 mV, with a gradual onset and offset that lasts for a minimum period of 1 minute. Each episode of ischemia must be separated by a minimum duration of at least 1 minute, during which the ST segment returns back to baseline (1x1x1 rule).
* Unwillingness or inability to follow the procedures outlined in the protocol.
* Subject is mentally or legally incapacitated.
* Neutrophil count \<2000 cells per microliter (a single repeat is allowed for eligibility determination).