Excretion balance, pharmacokinetics and metabolism of S 38844 after single oral dose administration of [14C]-S 38844 in healthy male volunteers.

S 38844 is a new investigational compound that may eventually be used for the
treatment of cardiovascular diseases through a selective reduction of the heart
rate. S 38844 is not registered as a drug but has been given to humans before.

Primary:
To assess after administration of a single oral dose of 75 mg S 38844
containing 55 *Ci (2.035 MBq) of [14C]-S 38844:
* The excretion balance of total radioactivity;
* The pharmacokinetics of total radioactivity in blood and plasma;
* The metabolite profile of S 38844 in plasma, urine and faeces;
* The pharmacokinetics of S 38844 and its metabolite S 41015 in plasma and
urine.

Secondary:
* To gain further information on the safety of S 38844;
* To perform a pharmacogenetic analysis of genes encoding for proteins involved
in absorption, distribution, metabolism and excretion (ADME).

Phase I, non-randomised, monocentre, open-label study in 6 healthy caucasian
male volunteers.

The volunteers will be once administered with S 38844 in the form of a syringe
in the mouth.

Procedures and assessments

Screening and follow-up:
clinical laboratory, full physical and mental examination, BP, HR, body
temperature, ECG; at eligibility screening: medical history, normal blood
(haematology, biochemistry) and urine (qualitative chemistry), drug screen,
HBsAg, anti HCV, anti-HIV *.

Observation period:
1 period in clinic from Day -1 to minimal Day 9 and maximum Day 13 after
administration of the study medication in the clinical research center in
Zuidlaren.

Blood sampling:
for pharmacokinetics : 18 venous blood samples for each volunteer, from just
prior to dosing up to 168 h (7 days) after dosing, according to the following
schedule: 0, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144,
168 h post IMP administration (volume comprised between 7 and 41.5 mL,
depending on sampling time).

Urine Sampling:
Urine from prior to dosing up to 168 h (7 days) after dosing and longer if
required, according to the following schedule:
For all subjects: ]-12-0h], ]0-4h], ]4-8h], ]8-12h], ]12-24h], ]24-48h],
]48-72h], ]72-96h], ]96-120h], ]120-144h], ]144-168h];
For each individual subject, part or all of the following time periods if
required: ]168-192h], ]192-216h], ]216-240h],]240-264h], ]264-288h],
]288-312h], ] 312-336h], ]336-360h], ]480-504h], ]648-672h].

Feces sampling;
Feces, from prior to dosing up to 168 h (7 days) after dosing and longer if
required, according to the following schedule:
For all subjects: ]-48-0h], ]0-24h], ]24-48h], ]48-72h], ]72-96h], ]96-120h],
]120-144h], ]144-168h];
For each individual subject, part or all of the following time periods if
required: ]168-192h], ]192-216h], ]216-240h],]240-264h], ]264-288h],
]288-312h], ] 312-336h], ]336-360h], ]480-504h], ]648-672h].

Safety assessments:
Adverse events throughout the study;
12-lead resting ECG and blood pressure;
Laboratory tests (haematology, blood biochemistry, urine biochemistry).

Pharmacogenetic assessments:
Pharmacogenetic assessments on genes encoding for proteins involved in
absorption, distribution, metabolism and
excretion (ADME): one 2.5-mL bloodsample at pre-dose on Day 01.

The volunteer will receive one dose of 75 mg S 38844 as a 20-mL clear
colourless drinking solution which will be dosed in the volunteers mouth by
means of syringe.

Blood draw, indwelling canula:
During this study 436 ml of blood will be drawn. One time an indwelling canula
will be used. The blood samplings on the other days of 7 in total will be
drawn by direct puncture of the vein. Blood sample for DNA tests: on Day 1 at
pre-dose a blood sample will be taken for possible DNA tests (this is not
mandatory).

Collection of urine and feces:
Urine and feces will be collected until 168 hours after administration of S
38844 (thus until Day 8) with a possible extension to Day 29 (672 hours). A
blank urine and feces sample will be obtained before drug administration.

Heart trace (ECG*s):
ECG*s will be made regularly: specifically on Days 0, on Day 1 at pre-dose, 3
and 24 hours after drug administration, before discharge and during post study
examination.

Adverse events:
In previous phase 1 studies, the overall safety and tolerability of S 38844
were considered satisfactory at all doses and in all conditions tested,
including a study with single administration up to 100 mg and repeated
administration up to 50 mg twice a day for 10 days. The most important adverse
events reported were: appearance of transient enhanced brightness in the eyes,
excessive slow heart rate, headache, fatigue, dizziness and gastro-intestinal
disorders.