Effect of Haemodialysis on the Pharmacokinetics of Ezogabine/Retigabine and Its N-acetyl Metabolite

Treatment Period 1: Subjects will be admitted on Day -1 when baseline assessments will be
performed. On Day 1 subjects will receive a single dose of 100mg ezogabine/retigabine
immediate release (IR) and dialysis will start 4 hours post-dose. Pharmacokinetic (PK)
samples will be collected up to approximately 68 hours post-dose.

Samples of dialysate will be collected in 0-1, 1-2, 2-3, and 3-4 hour (if available)
aliquots, timed from the start of dialysis. The volume of dialysate collected in each aliquot
will be recorded.

Four samples of predialyzer ("arterial" line) blood and four samples of postdialyzer
("venous" line) blood will be obtained during the haemodialysis procedure at approximately
one hour intervals starting immediately prior to the start of the procedure and finishing at
the end of the procedure.

Subjects will be discharged from the unit following the collection of the last PK sample.

Treatment Period 2: Subjects will be admitted on Day -1 when baseline assessments will be
performed. On Day 1 following the completion of their scheduled dialysis session subjects
will receive a single dose of 100mg ezogabine/retigabine IR. PK samples will be collected up
to approximately 68 hours post-dose.

Subjects will be discharged from the unit following the collection of the last PK sample.

In both treatment periods, PK blood samples will be obtained pre-dose, 0.5, 1, 1.5, 2, 2.5,
3, 4, 5, 6, 7, 8, 12, 16, 24, 36, 48, 60 and 68 hours (or just prior next dialysis session -
whichever is sooner) post-dose. Subjects will be discharged after the final post-dose draw.

Inclusion Criteria:

- Male or female 18 years or older, at the time of signing the informed consent.

- ESRD patients with minimal or no residual renal function and receiving stabilised
haemodialysis regimen.

- Body mass index with the range of 18-42 kg/m2 at screening.

- 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. Females on hormone replacement
therapy (HRT) and whose menopausal status is in doubt will be required to use one
of the contraception methods listed.

- Child-bearing potential and agrees to use one of the contraception methods
listed. Female subjects must agree to use contraception until at least 1 week
post-last dose.

- Male subjects with female partners of child-bearing potential must agree to use one of
the contraception methods listed. This criterion must be followed from the time of the
first dose of study medication until at least 1 week post-last dose.

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

Exclusion Criteria:

- Subjects with fluctuating or rapidly deteriorating condition that is not adequately
controlled by medications

- Subjects with signs of a clinically significant infection.

- Has active suicidal plan/intent or has had active suicidal thoughts in the past 6
months. Has history of suicide attempt in the last 2 years or more than 1 lifetime
suicide attempt.

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

- Clinically relevant laboratory or physical examination abnormalities (except for renal
function tests or deviation of clinical laboratory values that are related to renal
impairment).

- Subjects with blood pressure, after resting for ≥ 3 minutes, higher than 160/95 mmHg
or lower than 100/50 mmHg. The patients receiving anthihypertensive treatment need to
be on a stabilised treatment for three months.

- The screening ECGs measurements must be within the limit indicated in the protocol.

- Any significant arrhythmia which, in the opinion of the principal investigator and GSK
medical monitor, will interfere with the safety for the individual subject.

- History of hemoglobinopathy.

- A radiological test involving contrast dye within 4 weeks prior to screening.

- Poor peripheral venous access.

- 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).

- A positive pre-study drug/alcohol screen.

- 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, 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.

- Pregnant females

- Lactating females.

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

- Subject is mentally or legally incapacitated.