Pharmacokinetics of (deaminohydroxy)toremifene in humans: a new, selectiveestrogen-receptor modulator

Purpose: New selective estrogen-receptor modulators for the treatment and p revention of osteoporosis, cardiovascular disease and breast cancer are cur rently the focus of intense research. (Deaminohydroxy)toremifene (Z-2-[4-(4 -chloro-1,2-diphenyl-but-1-enyl)phenoxy]ethanol; FC-1271a) has been shown t o prevent bone resorption in rats while having no or weak estrogen-like eff ects on the uterus, which makes it a good candidate drug for osteoporosis p revention. Our purpose here was to examine the pharmacokinetics of (deamino hydroxy)toremifene in humans included in two phase-I studies. Methods: The first was a single-dose, dose-escalation study with 28 healthy male volunteers. Doses ranged from 10 mg to 800 mg. The second study was c onducted during a 12-week period with 40 healthy, post-menopausal women, wh o received repeated oral doses of 25-200 mg. Standard pharmacokinetic param eters were assessed. Results: In the single-dose study, time to reach peak concentration (t(max) ) ranged from 1.3 h to 4.0 h; peak concentration (C-max) ranged from 15 ng/ ml to 445 ng/ml, and the estimated terminal elimination half-life (mean +/- SD; t(1/2)) was 24.8 +/- 7.0 h. In the repeated-dose study, t(max) ranged from 1.9 h to 2.6 h at 6 weeks and from 2.5 h to 2.9 h at 12 weeks. C-max r anged from 295 ng/ml to 1043 ng/ml at 6 weeks and from 25 ng/ml to 1211 ng/ ml at 12 weeks. The average t(1/2) at all dose levels was 29.7 +/- 1.5 h (o verall mean +/- SD). Strong linear correlations between the dose and C-max and between the dose and the area under the curve were observed in both stu dies. Conclusion: Our results indicate that (deaminohydroxy)toremifene has pharma cokinetics suitable for single daily dosing. The prophylactic use of this a gent in women susceptible to development of osteoporosis, cardiovascular di sease and breast cancer could, therefore, be tested using a once-daily dosi ng schedule similar to those of other hormone-replacement therapy regimens.