Inclusion Criteria:


INCLUSION CRITERIA FOR COHORTS 1, 2, 3, 5 and 6.

A subject will be eligible for inclusion in cohorts 1, 2, 3, 5 and 6 of this study only if all of the following criteria apply:

1. Aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase and bilirubin less than or equal to 1.5 times Upper Limit of Normal, ULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin less than 35 percent).

2.Healthy as determined by the Investigator, based on a medical evaluation including medical history, physical examination, laboratory tests and Electrocardiogram (ECG). 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 GSK Medical Monitor agree that the finding is unlikely to introduce additional risk factors and will not interfere with the study objectives.

3.Male or female (of non child-bearing potential) between 18 and 65 years of age inclusive, at the time of signing the informed consent.

A female subject is eligible to participate only if she is of:
•Non-childbearing potential defined as pre-menopausal females with a documented tubal ligation (in which case the male partner should use an acceptable form of contraception as specified in section 8.1) or hysterectomy; or postmenopausal defined as 12 months of spontaneous amenorrhea [in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) > 40 million international units, MlU/ml and estradiol less than 40 picogrammes per millilitre (less than 140 picomoles per litre) is confirmatory]. [Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the contraception methods in Section 8.1 if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of post-menopausal status prior to study enrollment. For most forms of HRT, at least 2-4 weeks will elapse between the cessation of therapy and the blood draw; this interval depends on the type and dosage of HRT. Following confirmation of their post-menopausal status, they can resume use of HRT during the study without use of a contraceptive method.]

4.Male subjects must agree to use one of the contraception methods listed in Section 8.1. This criterion must be followed from the time of the first dose of study medication until 5 terminal half-lives post-last dose.

5.Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.

6.12 lead ECG without any clinically significant abnormality as judged by the Investigator, and QTc intervals corrected for Bazett ror Fredericia (QTcB and QTcF) less than450 milliseconds (msec)

7.Body weight greater than or equal to 50 kilogrammes (kg) (110 pounds, lbs) for men and greater than or equal to 45 kg (99 lbs) for women and Body Mass Index, BMI within the range 18-30 kilogrammes per squared metre (kg/m2) inclusive.

8.Non-smokers only– Negative urine cotinine test at screening, no history of smoking within 6 months of the start of the study, and with a total pack year history of less than or equal to 1 pack years.


INCLUSION CRITERIA FOR COHORT 4

A subject will be eligible for inclusion in cohort 4 of this study only if all of the following criteria apply:
1.Healthy as determined by the Investigator, based on a medical evaluation including medical history, physical examination, laboratory tests, ECG and Holter assessment at screening. A subject with a clinical abnormality or laboratory parameter outside the reference range for the population being studied may be included only if the Investigator and the GSK Medical Monitor agree that the finding is unlikely to introduce additional risk factors and will not interfere with the study objectives. A subject with a well controlled or mild medical condition (eg controlled hypertension, hypothyroidism adequately treated with replacement therapy, mild chronic obstructive pulmonary disease (COPD) requiring short acting bronchodilators only) may be included only if the Investigator and the GSK Medical Monitor agree that the condition is unlikely to introduce additional risk factors and will not interfere with the study objectives.

2.Male or female (of non child-bearing potential) over 65 years of age inclusive, at the time of signing the informed consent.

A female subject is eligible to participate only if she is of:
•Non-childbearing potential defined as pre-menopausal females with a documented tubal ligation (in which case the male partner should use an acceptable form of contraception as specified in section 8.1) or hysterectomy; or postmenopausal defined as 12 months of spontaneous amenorrhea [in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) > 40 million international units, MlU/ml and estradiol less than 40 picogrammes per millilitre (less than 140 picomoles per litre) is confirmatory]. [Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the contraception methods in Section 8.1 if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of post-menopausal status prior to study enrollment. For most forms of HRT, at least 2-4 weeks will elapse between the cessation of therapy and the blood draw; this interval depends on the type and dosage of HRT. Following confirmation of their post-menopausal status, they can resume use of HRT during the study without use of a contraceptive method.]


3.Male subjects must agree to use one of the contraception methods listed in Section 8.1. This criterion must be followed from the time of the first dose of study medication until 5 terminal half-lives post-last dose.

4.Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.

5.12 lead ECG without any clinically significant abnormality as judged by the Investigator and QTcB and QTcF less than 450 msec

6.Body weight greater than or equal to 50 kg (110 lbs) for men and greater than or equal to 45 kg (99lbs) for women and BMI within the range 18-35 kg/m2 inclusive.

7.For non-smokers only
• negative urine cotinine test at screening, no history of smoking within 6 months of the start of the study, and with a total pack year history of less than or equal to 1 pack years.

8.For smokers only
• a smoking history of greater than or equal to 5 pack years and currently smoking at least 5 cigarettes/day for the last 6 months


EXCLUSION CRITERIA

A subject will not be eligible for inclusion in this study if any of the following criteria apply:

1.A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of screening

2.Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).

3.Significant cardiac, pulmonary, metabolic, renal, gastrointestinal or other conditions that in the opinion of the investigator and/or GSK medical monitor, places the subject at an unacceptable risk as participant in this trial.

4.A positive pre-study drug/alcohol screen.

5.A positive test for human immunodeficiency virus (HIV) antibody.

6.History of regular alcohol consumption within 6 months of the study defined as an average weekly intake of greater than 21 units for males or less than14 units for females. One unit is equivalent to 8 g of alcohol: a half-pint (~240 ml) of beer, 1 glass (125 ml) of wine or 1 (25 ml) measure of spirits.

7.The subject has participated in a clinical trial and has received an investigational product within the following time period prior to the first dosing day in the current study: 3 months or 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer).

8.Exposure to more than four new chemical entities within 12 months prior to the first dosing day.

9.Use of prescription or non-prescription drugs, including vitamins, herbal and dietary supplements (including St John’s Wort) within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) prior to the first dose of study medication, unless in the opinion of the Investigator and GSK Medical Monitor the medication will not interfere with the study procedures or compromise subject safety.

10.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.

11.Where participation in the study would result in donation of blood or blood products in excess of 500 mL within a 56 day period.

12.Pregnant females as determined by positive serum or urine human Chorionic Gonadotrophin (hCG) test at screening or prior to dosing.

13.Lactating females.

14.Unwillingness or inability to follow the procedures outlined in the protocol.

15.Subject is mentally or legally incapacitated.

16.Consumption of red wine, seville oranges, grapefruit or grapefruit juice and/or pummelos, exotic citrus fruits, grapefruit hybrids or fruit juices from 7 days prior to the first dose of study medication.

17.For non-smokers only
• urinary cotinine levels indicative of smoking or history or regular use of tobacco
• or nicotine-containing products within 6 months prior to screening.

18.Blood pressure persistently greater than 150 over 90 (150/90) millimetres of mercury (mmHg) at screening.

• United Kingdom (click to view all sites in United Kingdom)
• GSK Investigational Site
  London, NW10 7EW; Recruiting;
  Contact: Steve J Warrington, Principal Investigator, .