Trimegestone

Trimegestone is a 19-norpregnane progestagen, with an in vitro affinity for the progesterone receptor approximately 6 times that of progesterone. Trimegestone has no significant androgenic, oestrogenic, mineralocorticoid, glucocorticoid, or antiglucocorticoid activity in vivo.

As oestrogens promote the growth of the endometrium, unopposed oestrogens increase the risk of endometrial hyperplasia and cancer. The addition of a progestagen reduces, but does not eliminate the oestrogen-induced risk of endometrial hyperplasia in non-hysterectomised women.

After single oral doses of 0.125 mg administered under fasting conditions to postmenopausal women, trimegestone is rapidly and completely absorbed with peak plasma concentrations of 2 to 5 ng/ml reached within 30 minutes. Food decreases the rate of absorption of trimegestone and reduces C_max by approximately 50% but does not affect the extent of its absorption when administered as Totelle. The absolute bioavailability after oral administration is approximately 100%. The terminal elimination half-life is approximately 17 hours (range 7 to 37 hours). The pharmacokinetics of trimegestone are dose proportional within the dose range of 0.0625 to 1 mg. After repeated once-a-day administration of 0.125 mg, steady state is reached by the third administration with average concentrations around 0.5 ng/ml and minimum plasma concentrations of 0.2 ng/ml. The pharmacokinetics of trimegestone after repeated administration can be predicted from single dose pharmacokinetics.

Trimegestone and its main metabolite trimegestone sulfate are highly bound to human plasma proteins (98%). Over the range of the concentrations reached after administration of the doses used in the clinical studies, the binding is constant and nonsaturable. The volume of distribution at steady state after intravenous administration is 1.8 l/kg.

Trimegestone is highly metabolised. The major metabolic pathway is sulfoconjugation; a minor pathway is oxidation via the CYP3A4 isoenzyme based on in vitro data. Trimegestone sulfate has 10 times greater plasma concentrations and a longer half-life (30 hours) than trimegestone, but less than one-tenth the progestin receptor-binding affinity of trimegestone. In plasma trimegestone sulfate is the main constituent of AUC after an oral single dose (approximately 55%). Unchanged trimegestone constitutes approximately 8% of AUC, while trimegestone glucuronide and 1- and 6-hydroxylated metabolites together constitute approximately 5% of AUC. After oral administration of radiolabeled trimegestone, 38% of the dose is excreted in urine while 54% is excreted in faeces. No unchanged trimegestone is excreted in urine.

Six (6) month toxicology studies in the rat and monkey showed no specific target organ toxicity other than effects associated with the progestomimetic action of the compound. Embryotoxicity studies were conducted with high dosages of trimegestone alone in rats and rabbits. Histological examinations in rabbits showed a dose dependent masculinization of some female foetuses at all doses tested. This effect has been reported for other progestagens, and the relevance of this observation to humans is unknown.