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- Title
Single and multiple ascending dose studies of a novel tissue-selective oestrogen receptor modulator, CHF 4227, in healthy postmenopausal women.
- Authors
Civelli, Maurizio; Preti, Alessandro Piero Monici; Cenacchi, Valentina; Rondelli, Ivano; Guastalla, Daniele; Tarral, Antoine; Dostert, Philippe; Guillevic, Yann; Homery, Marie-Claude
- Abstract
What is already known about this subject • CHF 4227 is a selective oestrogen receptor modulator (SERM) that compares favourably in efficacy and potency with raloxifene in preventing bone loss and lowering serum cholesterol concentrations in OVX rats. • The compound prevented the development of DMBA-induced mammary carcinoma in rats. • In preclinical studies, CHF 4227 differs from oestrogens and from others SERMs, such as levormeloxifene, in its lack of oestrogenic effects on uterine tissue. What this study adds • CHF 4227 is a well-tolerated SERM for postmenopausal women dosed once daily for 28 days. It appears to effect beneficially bone tissue and serum lipids without inducing oestrogenic actions on the endometrium, negative effects on fibrinolytic system, and without worsening menopausal symptoms, in particular hot flushes. • CHF 4227 is a promising agent for the treatment of several conditions in postmenopausal women. Aims We evaluated the tolerability, adverse events profile, pharmacokinetics, and pharmacodynamics of CHF 4227, a new selective oestrogen receptor modulator (SERM), in healthy postmenopausal women. Methods Two phase I studies were conducted according to a double-bind, placebo-controlled design. Subjects were randomized to receive six single (5–400 mg) or five multiple oral doses of CHF 4227 for 28 days (5–100 mg). Results No vaginal bleeding and no changes in either endometrial thickness or the placenta protein 14 marker were found after 4 weeks of treatment. The compound did not induce negative effects on the fibrinolytic system. After 28 days of treatment, CHF 4227 decreased both total and LDL cholesterol concentrations (maximum decreases from baseline of 17.4% (95% CI 7.0, 27.7) and 27.6% (95% CI 9.0, 46.3), respectively). Decreases in both serum and urinary type-I C-terminal collagen telopeptide were also observed producing maximum changes of 40.6% (95% CI 29.5, 51.7), and 41.7% (95% CI 20.3, 56.8), respectively. CHF4227 (5 and 10 mg) induced near maximal oestrogen-like effects on bone markers and serum lipids without causing hot flushes. The pharmacokinetics of CHF 4227 were characterized by a slow absorption, a long elimination half-life (31–42 h after single administration) and dose linearity with respect to C max and AUC up to 100 mg. Conclusions CHF 4227 is a well-tolerated SERM when administered once daily for 28 days. It is potentially active on bone resorption and serum lipids, without affecting the endometrium and without worsening hot flushes. CHF 4227 is a promising agent for the treatment of several conditions in postmenopausal women.
- Subjects
RALOXIFENE; PHARMACOKINETICS; DOSAGE forms of drugs; SELECTIVE estrogen receptor modulators; ESTROGEN receptors; RESORPTION (Physiology); BONE diseases; WOMEN'S health
- Publication
British Journal of Clinical Pharmacology, 2007, Vol 64, Issue 3, p304
- ISSN
0306-5251
- Publication type
Academic Journal
- DOI
10.1111/j.1365-2125.2007.02870.x