Excretion balance, pharmacokinetics and metabolism of S44819 after single administration of [14C]-S44819 in young healthy male volunteers. A phase 1 monocentre open-label study.

Our motricity and cognition are significantly determined by signal transmission
between nerve cells (neurons). A neuron activates other neurons by releasing
molecules called neurotransmitters that bind to proteins (called receptors) on
other neurons. An example of such a neurotransmitter is GABA
(gamma-amino-butyric acid). The transmission of signals could be potentiated or
reduced depending on levels of neurotransmitters in the brain. In certain
pathological circumstances, the GABA circuit can be overexpressed. This could
happen for example following an ischemic stroke (a cerebral event caused by the
occlusion of a cerebral artery and a lack of blood perfusion in the concerned
brain region). As a result of this, good motor and cognitive recovery may be
hindered.

S 44819 is an investigational compound that is being developed for the
treatment of patients presenting neurological deficits following an ischemic
stroke. S 44819 is being developed to improve the recovery of the brain after
such an event. S 44819 is a molecule that blocks some GABA receptors. As a
result, it decreases activity of the GABA circuit and could be beneficial to
enhance cognitive and motor recovery of patients suffering from stroke.

S 44819 is in development and is not registered as a drug but has been given to
humans before. So far, how quickly and to what extent S 44819 is absorbed,
distributed, metabolized (broken down) and excreted from the body (also called
pharmacokinetics) as well as the safety of S 44819 have already been studied
after a single oral administration at doses ranging from 10 mg to 800 mg in
healthy young volunteers and after 10-day repeated oral administrations at
doses ranging from 20 mg twice a day to 450 mg twice a day in healthy young and
elderly volunteers. S 44819 has already been administered to 133 healthy
volunteers; 88.7% were healthy male volunteers and 11.3% healthy female
volunteers; 25% of participants were aged >= 65 years. The treatment was well
tolerated.

The purpose of the study is to investigate the pharmacokinetics of S 44819. S
44819 is labeled with 14-Carbon (14C) and is thus radioactive (also called
radiolabeled). In this way, S 44819 and its metabolites can be traced in blood,
urine and feces. It will also be investigated to what extent S 44819 is safe
and tolerated.

The actual study will consist of 1 period during which the volunteer will stay
in the clinical research center for a minimum of 8 days (7 nights) to a maximum
of 15 days (14 nights). Thus, the volunteer will stay from the morning of Day
-1 (1 day before administration of the study compound; also called admission)
until at least Day 7.

Day 1 is the day of administration of study compound. The volunteer is expected
at the clinical research center in the morning of the day (Day -1) prior to the
day of administration of the study compound. The volunteer will be required not
to have consumed any food or drinks (with the exception of water) during the 10
hours prior to arrival in the clinical research center.

After administration of the study compound on Day 1, all of the volunteers
urine and feces will be collected during the entire research. The total amount
of radioactivity excreted in his urine and feces will be measured daily. From
Day 7 onwards, if the radioactivity levels in the volunteers urine and feces
are below pre-defined levels and/or if more than a pre-defined amount of
radioactivity has been excreted from his body, he will be allowed to leave the
clinical research center. The volunteer will leave the clinical research center
at the latest on Day 14. If the criteria for radioactivity as described above
are still not met on Day 14, he will have to continue the collection of all of
his urine and feces at home and return these to the clinical research center
every 2 days until Day 28 at the latest. These ambulatory visits are planned on
Days 16, 18, 20, 22, 24, 26, and 28 and will only take place if needed if the
criteria for radioactivity as described above are still not met.

The post-study screening will be planned within 3 to 5 days after the volunteer
has left the clinical research center, or within 3 to 5 days after he has
visited the clinical research center for the last time to return your urine and
feces, if this is necessary, or on Day 28 if the last ambulatory visit to
return his urine and feces is planned on that day. The appointment for the
post-study screening will be made with the volunteer as soon as it is known
when the study will end for him.

The participation to the entire study, from pre-study screening until the
post-study screening, will be a maximum of 50 days.

Back-up volunteer replacing a volunteer discontinued on Day 1
If the volunteer is a back-up volunteer and a volunteer that has received the
study compound discontinues on Day 1, he may be chosen to replace this
discontinued volunteer. In that case, he will be asked to stay in the clinical
research center for the rest of the day. The volunteer will then receive the
study compound the next day; that day will be the actual Day 1. As a result,
his stay in the clinical research center will last 1 day longer than described
above. Further, the volunteers participation to the entire study, from pre
study screening until the post-study screening, will be a maximum of 51 days.

The volunteer will receive a single dose of 180 mg radiolabeled S 44819 as an
oral suspension in sitting position. This will be immediately followed by the
ingestion of 150 milliliters (mL) of water.

The volunteer will receive a single dose of 180 milligrams (mg) radiolabeled S
44819 as an oral suspension; the suspension is a liquid with undissolved
powder.

All potential drugs cause adverse effects; the extent to which this occurs
differs. Three clinical studies have been conducted in healthy volunteers with
S 44819 in which single doses up to 800 mg (79 healthy volunteers) and repeated
doses up to 450 mg (54 healthy volunteers) were well tolerated. A total of 133
healthy volunteers received S 44819. No severe side effect was reported by
investigators. The most frequently observed side effect was headache, which was
reported by 3.3% of the subjects followed by dyspepsia (2.0%) and diarrhea
(2.0%).

The volunteer should be aware that the aforementioned adverse effects and
possibly other, still unknown adverse effects, may occur during the study.
However, with the doses used in this study no serious adverse effects are
expected.

In this study radiolabeled S 44819 will be used. The amount of radioactivity in
this dose will be approximately 1.58 MBq (MBq = megaBecquerel, this is a unit
to express the amount of radioactivity in the study compound). The average
environmental background radiation burden in The Netherlands is approximately 2
mSv per year (mSv = milliSievert, this unit indicates the burden on the human
body; thus the effect on the human body of the amount of radioactivity
administered). The additional radiation burden in this study due to the
administration of approximately 1.58 MBq radiolabeled S 44819 is calculated to
be 0.5 mSv. This is approximately 25% of the average annual radiation burden.

Procedures: pain, minor bleeding, bruising, possible infection