Assessment of the Single Dose Pharmacokinetics and Tolerability of Sativex in Patients With Impaired Hepatic Function and Healthy Patients

Inclusion Criteria:

- Subject is aged 18 years or above.

- Subject is willing and able to give informed consent for participation in the study
(see Section 14.2).

- Male or female subjects.

- All females must have negative pregnancy test results at screening and baseline.

- Vital signs (after five minutes resting measured in the supine position) must be
within the following ranges:

- Body temperature between 35.0-37.5 °C

- Systolic blood pressure, 90-150 mmHg

- Diastolic blood pressure, 60-90 mmHg

- Pulse rate, 40-99 beats per minute (bpm) Blood pressure and pulse will be taken again
in a standing position. After two minutes standing, there shall be no more than a 20
mmHg drop in systolic or 10 mmHg drop in diastolic blood pressure, associated with
clinical manifestation of postural hypotension.

- Subjects must weigh at least 50 kg and have a BMI between 19 and 42 kg/m2 to
participate in this study.

- Patients with impaired hepatic function must be compliantly on a stable dose of
medication and/or treatment regimen (in the opinion of the investigator) for at least
4 weeks prior to the dosing day with no foreseeable plans for change.

- Subject is able (in the Investigators opinion) and willing to comply with all study
requirements.

- Willing and able to communicate well with the Investigator.

- Subject is willing for his or her name to be notified to the responsible authorities
for participation in this study, as applicable in individual countries.

- Subject is willing to allow his or her primary care practitioner and consultant, if
appropriate, to be notified of participation in the study.

Groups 1 and 2 (mild and moderate hepatic impairment)

- Clinical features consistent with a confirmed clinical diagnosis of mild and moderate
liver impairment.

- Child-Pugh clinical assessment score consistent with degree of hepatic impairment.

- Clinical evidence of stable hepatic impairment, defined as no clinically significant
change in disease status within the last 30 days, as documented by the patients'
recent medical history.

- Otherwise considered healthy in general as determined by past medical history,
physical examination, vital signs, ECG, and laboratory tests at screening.

- Platelet count > 50,000 X 109/L at screening and baseline.

- Willing to maintain a stable dose of any, not prohibited, medication throughout the
study.

Group 3 (severe hepatic impairment)

- Patients presenting at least one clinical sign consistent with a clinical diagnosis
of severe liver impairment.

- Child-Pugh clinical assessment score consistent with degree of hepatic impairment.

- Platelet count > 30,000 X 109/L at screening and baseline.

- Willing to maintain a stable dose of any, not prohibited, medication throughout the
study.

Group 4 (healthy controls)

- In good health as determined by past medical history, physical examination, vital
signs, ECG, and laboratory tests at screening.

- Healthy male or female subjects, matched with respect to age (±10 years), weight
(±10% BMI) and sex to the severe or most severe evaluable patients.

- No clinical evidence of liver disease or liver injury as indicated by clinically
significant abnormal liver function tests such as aspartate aminotransferase, alanine
aminotransferase, γ-glutamyl-transpeptidase, alkaline phosphatase, or serum bilirubin
two times above the upper limit of the normal range.

Exclusion Criteria:

- Donation or loss of 400 mL or more of blood within eight weeks prior to dosing.

- Significant concomitant illness within the two weeks prior to dosing.

- Resting heart rate <40 bpm.

- History of autonomic dysfunction.

- History of clinically significant drug allergy; a known hypersensitivity to the study
drug or drugs similar to the study drug.

- Any surgical or medical condition (other than hepatic impairment) which might
significantly alter the absorption, distribution, metabolism or excretion of drugs,
or which may jeopardize the subject in case of participation in the study.

- Any history of significant bleeding and haemorrhagic tendencies. However, subjects
with a history of bleeding tendencies secondary to hepatic impairment will be
excluded based on Principal Investigators' discretion.

- History of immunocompromisation, including known history of human immunodeficiency
virus seropositivity.

- History of drug abuse within the 12 months prior to dosing, or evidence of such abuse
as indicated by the laboratory assays conducted during the screening or baseline
evaluations.

- Unwilling to abstain from alcohol during this study.

- Currently receiving a prohibited or restricted medication and unwilling to stop or
comply with restriction for 14 days prior to the screening visit and for the duration
of the study.

- Currently using or has used cannabis, cannabinoid-based medications (e.g. Marinol,
Nabilone, Cannador), or Acomplia (rimonabant) or taranabant within 30 days of study
entry and unwilling to abstain for the duration of the study.

- A known or suspected history or family history of schizophrenia, other psychotic
illness, severe personality disorder or other significant psychiatric disorder other
than depression associated with underlying condition.

- A history of uncontrolled epilepsy as evidenced by one or more seizures in the last
12 months.

- Significant cardiac disease, e.g. has experienced myocardial infarction (MI) (if the
screening ECG reveals patterns consistent with a MI and the date of the event cannot
be determined, then the subject can enter the study at the discretion of the
Investigator and/or local medical monitor) or clinically relevant cardiac dysfunction
within the last six months, or any of the following within the last six months:

- had a coronary artery bypass surgery or percutaneous coronary intervention,

- has unstable angina or has had stroke,

- unstable heart insufficiency (New York Heart Association grade III-IV),

- has a cardiac disorder that, in the opinion of the Investigator, would put the
subject at risk of a clinically relevant arrhythmia or MI, or has a secondary or
tertiary atrioventricular block.

- Had liver surgery (including transplantation) within the last six months.

- Has significant renal disease or significantly impaired renal function with a
creatinine clearance below 50 mL/min for Group 1 and 2, or below 40 mL/min for Group
3.

- Female subjects of child bearing potential and male subjects whose partner is of
child bearing potential, unless willing to ensure that they or their partner use
effective contraception, for example, oral contraception, double barrier or
intra-uterine device, during the study and for three months thereafter (however, a
male condom should not be used in conjunction with a female condom as this may not
prove effective).

- Female subject who is pregnant, lactating or planning pregnancy during the course of
the study and for three months thereafter.

- Any clinically significant abnormal findings in physical or oral examination, ECG or
laboratory evaluations (not consistent with known clinical disease) which, in the
opinion of the Investigator, may put the subject at risk, influence the result of the
study, or the subjects' ability to participate in the study.

- Subjects who are unwilling to abstain from smoking from midnight on Day -1 to four
hours post dose Day 1.

- Subjects who consume more than five caffeinated beverages per day (e.g. five cups of
tea or coffee or cans of cola) or who are unwilling to abstain from consumption of
caffeine-containing food and beverages throughout the period of in-patient
confinement.

- Unwilling to abstain from donation of blood during the study.

- Travel outside the country of residence planned during the study.

- Subjects previously enrolled into this study.

- Any known or suspected hypersensitivity to cannabinoids or any of the excipients of
the investigational medicinal product (IMP).

- Subjects who have received an IMP within 30 days or five times the half-life of the
IMP (whichever is greater) prior to the screening visit.

Groups 1, 2, and 3 (hepatic impairment)

- Symptoms or history of Stage III or worse degree of encephalopathy.

- Clinical evidence of severe ascites.

- Any evidence of acute progressive liver disease.

- Patients with clinically abnormal prothrombin time will be excluded based on the
Principal Investigators' discretion.

Group 4 (healthy controls)

- A positive Hepatitis B surface antigen or Hepatitis C test result.

- History of alcohol abuse within the 12 months prior to dosing or evidence of such
abuse, as indicated by the laboratory assays conducted during the screening or
baseline evaluations.

- Use of any prescription medication within 14 days prior to dosing except for hormonal
contraceptives.

- Use of over-the-counter medications or vitamins within 14 days prior to dosing
(except for the occasional use of paracetamol).