Rapid suppression of plasma testosterone levels and tumor growth in the dunning rat model treated with degarelix, a new gonadotropin-releasing hormone antagonist.

Degarelix (FE 200486) is a member of a new class of water-soluble (>50 mg/ml) gonadotropin-releasing hormone (GnRH) antagonists in clinical development for prostate cancer. Upon subcutaneous administration, degarelix forms a gel that results in a sustained release of the compound into the circulation, immediately blocking GnRH receptors in the pituitary and inducing a fast and sustained suppression of gonadotrophin secretion in rats and primates. One of the few animal models of prostate adenocarcinoma is the Dunning R-3327H rat carcinoma transplanted into Copenhagen rats. The growth of the Dunning tumor can be inhibited by various treatments reported to be effective in the clinic, such as GnRH superagonists, antiandrogens, 5-alphareductase inhibitors, tyrosine kinase inhibitors, and surgical castration. We report in this study that degarelix produces a fast and sustained suppression of the pituitary gonadal axis in rats and a similar inhibition of tumor growth compared with surgical castration in the Dunning R-3327H rat carcinoma model. First, degarelix as been compared with d-Trp(6)-luteinizing hormone-releasing hormone and surgical castration on a short-term study (2 months); and second, degarelix has been compared with leuprolide and surgical castration on a long-term study (12 months). In both studies, degarelix demonstrated a sustained inhibition of tumor growth at least comparable with surgical castration. These data provide a convincing profile of degarelix as a potential candidate for the clinical management of sex steroid-dependent pathologies, such as prostate cancer, where long-term reversible chemical castration is required.

Levormeloxifene: safety, pharmacodynamics and pharmacokinetics in healthy postmenopausal women following single and multiple doses of a new selective oestrogen receptor modulator.

AIMS: The safety, pharmacodynamics and pharmacokinetics of levormeloxifene, a selective oestrogen receptor modulator (SERM), were investigated in postmenopausal women following single doses and multiple dosing once daily up to 56 days. METHODS: The two randomized, double-blind, placebo controlled studies of six single ascending doses and at four multiple dose levels, respectively, included a total of 104 healthy postmenopausal women. Safety assessments comprised vital signs, ECG, haematology, clinical chemistry and reporting of adverse events. The pharmacodynamic properties were investigated after multiple dosing by assessment of the short-term effects on bone and lipid metabolism and on the hypothalamic-pituitary axis. Blood samples for pharmacokinetic analysis were collected at intervals until 648 h (27 days) after single and multiple dosing. RESULTS: Levormeloxifene was tolerated well after single doses in the range of 2.5--320 mg and multiple once daily dosing in the range of 20--160 mg. Adverse events reported were generally mild or moderate. The most frequent adverse events after multiple dosing were headache, abdominal pain and leukorrhea with the highest frequency reported after the highest daily dose of 160 mg levormeloxifene. Five weeks of treatment with 20--160 mg levormeloxifene and 8 weeks of treatment with 40 or 80 mg levormeloxifene reduced the biochemical marker of bone turnover, the collagen I C-terminal telopeptide (CrossLaps) by 44.4% [95% CI: 11.3, 65.1] and 35.5% [95% CI: 14.0, 51.6], respectively, without any dose-dependent decrease in the studied dose range. The total cholesterol and LDL-cholesterol concentrations were significantly reduced by 19--25% and 28--35%, respectively, when compared with placebo. HDL-cholesterol and triglyceride concentrations were not affected. An oestrogen-like effect on the hypothalamic-pituitary axis was observed with approximately 50% reductions of FSH and LH after 8 weeks of treatment. No clinically significant changes of other safety variables were observed. The pharmacokinetic analysis demonstrated a rapid absorption (mean tmax: 2--3 h), a slow elimination (mean t1/2: 4.8--8.4 days) and dose linearity of Cmax and AUC for doses up to 160 mg. As expected for a drug with slow elimination given frequently, the relative fluctuation around the steady state plasma concentration was small and the drug accumulation considerable (RA: 3--5). CONCLUSIONS: Short-term administration of levormeloxifene in postmenopausal women was well-tolerated at doses that elicited a favourable pharmacodynamic response suggesting oestrogen-like bone preserving and antiatherogenic effects. Little variation of peak-trough plasma concentrations was observed during daily administration due to a plasma half-life of approximately 1 week.