Study to Evaluate Darapladib in Moderately Hepatically Impaired Subjects

This study is an open-label, non-randomised study to assess the pharmacokinetics and
safety/tolerability of repeat oral 40 mg doses of darapladib in subjects with moderate
hepatic impairment (as defined by a Child-Pugh score of 7-9) in comparison to matched
healthy volunteers.

The hepatically impaired and healthy volunteer groups will receive repeat oral doses of
darapladib for 10 consecutive days. The pharmacokinetics of darapladib and its metabolites
will be evaluated. The effect of liver impairment on the plasma protein binding of
darapladib and metabolites will also be determined as data permit. Safety will be assessed
by clinical laboratory tests (hematology, chemistry and urinalysis), vital signs (blood
pressure and heart rate measurements), 12-lead electrocardiograms (ECGs) and monitoring for
adverse events (AEs).

Subjects will be housed in the clinical unit from the evening before first dose until 24
hours after the final dose of 10 days of repeat dosing. A follow-up period will include 2
visits, one of which will be conducted approximately 10-14 days from the last dose of study
drug and the second visit will be 35 days +/- one week after the last dose of study drug

Inclusion Criteria:

- A male or female is eligible to enter and participate in this study if he/she is a
healthy subject OR a moderately hepatically impaired subject with a Child-Pugh score
of 7-9.

- Age between 18 and 65 years inclusive, at the time of signing the informed consent.

- Body mass index (BMI) within the range of 19-37kg/m2

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

- QTcB < 480 msec in all subjects, including those with bundle branch block at
screening ECG

- Healthy subjects only: AST, ALT, alkaline phosphatase and bilirubin less than or
equal to 1.5xULN (isolated bilirubin greater than 1.5xULN is acceptable if bilirubin
is fractionated and direct bilirubin less than 35%)

Exclusion Criteria:

- Hepatically Impaired Group:

- A positive pre-study drug/alcohol screen, except where subject has prescription for
pain or anxiolytic medication that would cause positive test.

- Subjects using any concurrent prohibited medication, and/or receiving concurrent
therapy that cannot be safely discontinued and is not approved by the investigator

- 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.

- Consumption of grapefruit or grapefruit juice > 8oz within 7 days prior to first dose
of study medication.

- Currently receiving oral or injectable strong CYP3A4 inhibitor(s)

- Subjects with any predisposing condition including malabsorption syndromes that might
interfere with the absorption, distribution, metabolism, or excretion of drugs
(except for hepatic impairment) or any previous gastrointestinal (GI) surgery (except
appendectomy or gall bladder removal more than three months prior to the study).

- 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 medical
monitor, contraindicates their participation.

- History of anaphylaxis, or anaphylactoid (resembling anaphylaxis) reactions, or
severe allergic responses.

- Subjects with fluctuating or rapidly deteriorating hepatic function. Subjects should
be medically stable in the opinion of the principal investigator, evidenced by liver
function tests as well as clinical signs and symptoms for 30 days before the study.

- Subjects with advanced ascites (Grade 3) or subjects with moderate or severe
encephalopathy (Grade 3 or 4) as judged by the investigator.

- History of sensitivity to heparin or heparin-induced thrombocytopenia (if heparin is
to be used for flushing a cannula).

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

- Use of oral, injected and implanted hormonal methods of contraception for female
subjects.

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

- Lactating females.

- Subjects with a positive HIV antibody test.

- Subjects with creatinine clearance less than or equal to 60 mL/min (calculated by the
Cockcroft-Gault Formula)

- Subjects who, within the past two months, have had a history of drug or alcohol abuse
or any indication of regular use of more than two units per day

- Subjects with signs of active infection with constitutional symptoms.

- Subjects with esophageal variceal bleeding, unless if banded and stable, within the
past 6 months.

- Subjects with a known immediate or delayed hypersensitivity reaction or idiosyncrasy
to drugs chemically related to the study drug.

- Subjects with any history of heart failure.

- Subjects with unstable coronary heart disease (unstable angina, acute coronary
syndrome, or unstable cardiac rhythm) within the past 6 months.

- Subjects with any other medical condition which, in the judgement of the investigator
and medical monitor, could jeopardize safety or welfare of the subject and/or the
integrity of the data derived from that subject.

- Severe asthma that is poorly controlled on pharmacotherapy

- Subjects with a risk of non-compliance in following directions or adhering to study
restrictions or any subject that the principal investigator deems unsuitable for
continuation in study conduct.

- Healthy Volunteer matched group:

- A positive pre-study drug/alcohol screen.

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

- A positive test for HIV antibody.

- History of regular alcohol consumption within 6 months of the study

- 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, or 5 half-lives of the investigational product (whichever is longer).

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

- 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 medical
monitor the medication will not interfere with the study procedures or compromise
subject safety.

- Currently receiving oral or injectable strong CYP3A4 inhibitor(s)

- Consumption of grapefruit or grapefruit juice > 8oz within 7 days prior to first dose
of study medication.

- Alcohol or drug abuse within the past 6 months, or current mental condition
(psychiatric disorder, senility or dementia), which may affect study compliance or
prevent understanding of the aims, investigational procedures or possible
consequences of the study

- 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 medical
monitor, contraindicates their participation.

- History of anaphylaxis, or anaphylactoid (resembling anaphylaxis) reactions, or
severe allergic responses.

- Severe asthma that is poorly controlled on pharmacotherapy

- History of cholecystectomy or biliary tract disease, or a history of liver disease
with elevated liver function tests of known or unknown etiology.

- History of sensitivity to heparin or heparin-induced thrombocytopenia (if heparin is
to be used for flushing a cannula).

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

- Use of oral, injected and implanted hormonal methods of contraception for female
subjects.

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

- Lactating females.

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

- Subject is mentally or legally incapacitated.