A human phase 0, microdose pharmacokinetic study of [14C]-Org 201745-0, [14C]-Org 244378-0 and [14C]-Org 245021-0 in post-menopausal female volunteers

Currently marketed female contraceptives consist of a steroidal progestagenic
compound, either combined with a steroidal estrogenic compound or given as a
progesterone only product. Due to their steroidal nature, these compounds, and
their metabolites, are often not specific for either the progesterone receptor
or the estrogen receptor. It is thought that part of the undesirable
side-effects observed with the use of current contraceptives is due to
inappropriate agonism or antagonism of the androgenic, mineralocorticoid or
glucocorticoid receptors. This results in undesired effects on carbohydrate
metabolism, hepatic function, lipid metabolism and thyroid function. In
addition, estrogen-related side effects are cardiovascular effects secondary to
hemostatic disturbance.
Org 201745-0, Org 244378-0 and Org 245021-0 are potent, metabolically stable,
orally active non-steroidal selective progestagens with high selectivity for
the progesterone receptor which are being developed as an estrogen-free female
oral contraceptive suitable for once-a-week administration.

1)To assess the preliminary pharmacokinetics of [14C]-Org 201745, [14C] Org
244378 and [14C] Org 245021 when administered as a sub-therapeutic dose by the
oral route to healthy post-menopausal female volunteers.

2) To evaluate the safety and tolerability of a single oral administration of
[14C-Org 201745, [14C] Org 244378 and [14C]-Org 245021 to healthy
post-menopausal female volunteers

a phase 0, open label, single oral dose study in post-menopausal female
subjects with the compounds [14C]-Org 201745, [14C] Org 244378 and [14C]-Org
245021; each compound will be administered as a sub-therapeutic dose to 6
female subjects

[14C]-Org 201745, [14C]-Org 244378 and [14C]-Org 245021 microdose

As ORG 244378-0 en ORG 245021-0 will be administered to man for the first time
in this study, adverse effects in man have not been reported up to now. The
amount of study drug that is administered in this study is less than 1/100 th
of the dose at which an effect is expected in the human body. With this *micro
dose* the chance of unfavorable effects on your health may be considered
minimal.

The two compounds have not been previously studied in humans. Safety studies
conducted in rats demonstrated that the two compounds were well tolerated at a
dose 1000-fold higher than the intended human microdose in this study.

In studies conducted in rats with ORG 244378-0 the following changes were
observed: increased weight, red blood cell distribution width, total protein,
cholesterol and triglycerides in blood.
In studies conducted in rats with ORG 245021-0 the following changes were
observed: slight increased weigth and increased level of triglycerides.

ORG 201745-0 has been administered to man recently for the first time in doses
from 0.1 to 1 mg. The results from this ongoing study show that ORG 201745-0
can be administered to man safely and is well-tolerated.