An open-label, single-arm study to determine the excretion balance and metabolic disposition of [14C]GW642444 administered as a single dose of an oral solution to healthy male volunteers

The drug to be given GW642444 is a new, investigational compound that may
eventually be used in the treatment of asthma and Chronic Obstructive Pulmonary
Disease (COPD).

In asthma and COPD, difficulty in breathing results from one or more different
processes including spasm of the bronchial tubes, swelling of the bronchial
tubes, mucus that is difficult to clear from the bronchial tubes, and
thickening of the bronchial wall.
The compound GW642444 is expected to be a long acting bronchodilator and as
such will make it easier to breath for people suffering from asthma and COPD.
Currently available medications require twice-daily administration. GW642444
should have the advantage of requiring only once-daily administration in the
treatment of asthma and COPD. This new compound is not registered as a drug but
has been given to humans before.

Primary:
To compare total radioactivity (drug-related material) in plasma relative to
parent plasma GW642444 concentration following a single oral dose (200µg) of
[14C]-GW642444 in healthy male subjects.
To determine the rate and extent of excretion of total radioactivity in urine
and faeces and the total recovery of radioactivity, after a single oral dose
(200µg) of [14C]-GW642444 to healthy male subjects.

Secondary:
To generate samples with which to characterise and quantify the metabolic
profile of GW642444 in plasma, urine, duodenal bile and faeces following
administration of a single oral dose (200µg) of [14C]GW642444 to healthy male
subjects. These investigations will be conducted as a separate study.
To generate samples with which to provide a relative estimate of GW642444
metabolites in human bile, following administration of a single oral dose
(200µg) of [14C]GW642444 to healthy male subjects. These investigations will be
conducted as a separate study.
To evaluate the safety and tolerability of a single oral dose (200µg) of
[14C]-GW642444 in healthy male subjects.

Design:
An open-label ADME study in six healthy male subjects receiving a single oral
dose of GW642444 containing 2 *Ci (0.074 MBq) of [14C]-GW642444.

Procedures and assessments
Screening and follow-up:
Clinical laboratory, vital signs, physical examination, 12-lead ECG; at
eligibility screening: medical history, 12-hour Holter, alcohol urine test,
drug screen, HBsAg, anti HCV, anti-HIV 1/2; brief physical examination, alcohol
urine test, drug screen and clinical laboratory to be repeated upon admission.

Observation period:
One period in clinic from -17 h up to 168 h (Day 8) after drug administration
with possible extension to Day 11 if discharge criteria (less than 1% of total
dose excreted in urine and faeces combined for 2 consecutive 24 h periods) are
not met. If discharge criteria are still not met on Day 11, collection of urine
and or faeces at home until Day 14 will be requested.

Blood sampling:
For pharmacokinetics of GW642444 and total radioactivity: once at screening and
on Day -1 and pre-dose and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 2.5, 3, 3.5, 4, 5,
6, 12, 24, 48, 72, 96, 120, 144 and 168 h post-dose. For metabolite profiling:
pre-dose and 0.5, 1.5, 3 and 24 h post-dose.
For genotyping: once on Day -1.

Urine sampling:
For pharmacokinetics: pre-dose and 24 h intervals until discharge (one aliquot
of each urine collection will be taken for metabolite profiling).

Faeces sampling:
For pharmacokinetics: pre-dose and 24 h intervals until discharge (one aliquot
of each faeces collection will be taken for metabolite profiling).

Entero test (bile sampling):
For bile sampling: from 2 h post dose until 6.5 h post dose.

Safety assessments:
Adverse events: throughout the study; vital signs and 12-lead ECG: pre-dose (in
triplicate) and 0.5, 1, 2, 6 and 12 h post-dose.

Bioanalysis:
Analysis of plasma GW642444 samples using validated methods by Sponsor,
analysis of total radioactivity in urine and faeces using validated methods by
PRA, analysis of total radioactivity in plasma by Sponsor, quick counts by PRA,
metabolite profiling by Sponsor,
genotyping by Sponsor.

Active substance: GW642444 and [14C]-GW642444

Procedures:
Pain, light bleeding, haematoma, possible an infection.