A Study to Assess the Effects of Fluticasone Furoate and GW642444M Combination in Healthy Subjects and in Subjects With Mild, Moderate or Severe Hepatic Impairment.

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

Suffered a lower respiratory tract infection in the 4 weeks before the screening visit.

Taken oral corticosteroids less than 8 weeks before the screening visit.

Taken inhaled, intranasal or topical steroids less than 4 weeks before the screening visit.

Have a known sensitivity to corticosteroids and/or long acting beta agonists.

A positive pre-study drug/alcohol screen.

A positive test for HIV antibody.

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: 30 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer).

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

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.

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

Pregnant females as determined by positive serum or urine hCG test at screening or prior to dosing.

Lactating females.

The subject has been treated for or diagnosed with depression within six months of screening or has a history of significant psychiatric illness.

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

Subject is mentally or legally incapacitated.

History of sensitivity to heparin or heparin-induced thrombocytopenia.

Subjects who have asthma or a history of asthma.

History of severe milk protein allergy.

Subjects with a smoking history of \>10 cigarettes per day or regular use of tobacco- or nicotine-containing products, within 6 months prior to screening.

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.

Healthy subjects

If, in the opinion of the examining physician, an unstable cardiovascular, renal, hepatic, pulmonary, endocrine, metabolic, neurological, haematological or gastrointestinal condition is present or any other medical condition which the investigator considers sufficiently serious to interfere with the conduct, completion, or results of this trial or constitutes an unacceptable risk to the subject.

Subjects with any predisposing condition that might interfere with the absorption, distribution, metabolism or excretion of drugs or any previous gastrointestinal (GI) surgery (except appendectomy or cholecystectomy more than three months prior to the study) condition which the investigator considers sufficiently significant to interfere with the conduct, completion, or results of this trial or constitutes an unacceptable risk to the subject.

Haemoglobin values \<12.9g/dL for males and \<11.4g/dL for females.

A past history or current symptoms of significant hepatic or renal disease, pancreatitis or acute cholecystitis which the investigator considers sufficiently significant to interfere with the conduct, completion, or results of this trial or constitutes an unacceptable risk to the subject.

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

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

History of regular alcohol consumption within 6 months of the study defined as:

• An average weekly intake of \>21 units for males or \>14 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.

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 inhibitor) 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. In particular subjects taking steroids or medications that significantly inhibit P450 CYP3A4 (e.g. ketoconazole) must not be included in this study.

Hepatically Impaired Subjects

If in the opinion of the examining physician, an unstable cardiovascular, renal, pulmonary, endocrine, metabolic, neurological, haematological or gastrointestinal condition is present or any other significant medical condition which the investigator considers sufficiently serious to interfere with the conduct, completion, or results of this trial or constitutes an unacceptable risk to the subject.

Severe ascities (Child-Pugh ascites score of 3) upon clinical exam, including physical exam and abdominal ultrasound at screening. Subjects identified to have moderate ascities by ultrasound examination may be included at the discretion of the Investigator with prior agreement from the sponsor.

History of oesophageal bleeding within the last 6 months before dosing.

Significant hepatic encephalopathy, degree of CNS impairment or other signs of hepatic function deterioration which the investigator considers sufficiently serious to interfere with the informed consent, conduct, completion, or results of this trial or constitutes an unacceptable risk to the subject.

Patients at risk of requiring a transfusion during the study period, or has haemoglobin \< 9 g/dL, or has underlying coronary artery disease (or other clinical condition) in which a reduction in haemoglobin associated with FF/GW642444M administration might be expected to cause clinical deterioration.

Evidence of current significant infection (e.g. spontaneous bacterial peritonitis, pneumonia etc.).

Subjects who develop symptoms such as infections or haemorrhage between screening and dosing must not be included in the study.

Fluctuating or rapidly deteriorating hepatic function (such as, but not limited to, rapidly increasing ascites, rapidly deteriorating mental status, deteriorating hepatic function based on prothrombin time \[PT\], albumin, total bilirubin). Assessment of the stability of the subject's hepatic function will be at the discretion of the Principal Investigator.

Subjects with significant renal insufficiency as defined by estimated creatinine clearance of \<50 ml/min, using the Cockcroft and Gault equation.

Subjects with a diagnosis of primary biliary disease such as cholestasis or sclerosing cholangitis.

Subjects who need to take any concomitant medication, either prescribed or over-the-counter, which may in the opinion of the Investigator, interfere in any way with the study procedure or be a safety concern (see Section 9 for the list of permitted concurrent medications). In particular subjects taking medications that significantly inhibit P450 CYP3A4 (e.g. ketoconazole) must not be included in this study.

Subjects who, within the past six months, have had a history of significant drug abuse or alcohol abuse.

What this study is about