Single and multiple ascending dose studies of a novel tissue-selective oestrogen receptor modulator, CHF 4227, in healthy postmenopausal women.
OBJECTIVE
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.
Civelli
Maurizio
M
Research & Development Division, Chiesi Farmaceutici S.p.A., Via Palermo 26/A, 43100 Parma, Italy.
Preti
Alessandro Piero Monici
AP
Cenacchi
Valentina
V
Rondelli
Ivano
I
Guastalla
Daniele
D
Tarral
Antoine
A
Dostert
Philippe
P
Guillevic
Yann
Y
Homery
Marie-Claude
MC
D001578:Benzopyrans / Q000008:administration & dosage* / Q000494:pharmacology; D001862:Bone Resorption; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004717:Endometrium / Q000187:drug effects; D005260:Female; D005602:France; D019584:Hot Flashes; D006801:Humans; D008055:Lipids / Q000097:blood; D010880:Piperidines / Q000008:administration & dosage* / Q000494:pharmacology; D017698:Postmenopause / Q000187:drug effects*; D020845:Selective Estrogen Receptor Modulators / Q000008:administration & dosage* / Q000494:pharmacology
C466797:3-(4-methoxy)phenyl-4-((4-(2-(1-piperidinyl)ethoxy)phenyl)methyl)-2H-1-benzopyran-7-ol; D001578:Benzopyrans; D008055:Lipids; D010880:Piperidines; D020845:Selective Estrogen Receptor Modulators