A double-blind study of MPV-2213ad, a novel aromatase inhibitor, in healthy male subjects.
OBJECTIVE
Novel aromatase inhibitors are developed with requirements of high potency and selectivity for the aromatase enzyme. The hormonal effects of a new, non-steroidal competitive inhibitor of the aromatase enzyme, MPV-2213ad, were investigated in this study.


METHODS
The study was conducted as a double-blind, placebo controlled phase I study, where 32 healthy male volunteers were randomized to receive a single oral dose of either 0.3, 3 or 100 mg of MPV-2213ad or placebo. Serum concentrations of estradiol (E2), testosterone, follicle stimulating hormone (FSH), luteinizing hormone (LH), cortisol and aldosterone were determined from samples taken 0, 4, 8 h and 12 h during the day of drug administration and 1, 2, 4 and 7 days after drug intake. The individual diurnal variation of circulating hormone concentrations was determined in all participants at 0, 4, 8 h and 12 h on the day before drug intake. Specimens for hematological and biochemical analyses were also collected.


RESULTS
A dose-dependent and statistically significant (P < 0.001) decrease in serum E2 concentrations was induced by MPV-2213ad. Lowest mean values were observed 8-12 h after drug administration and at 24 h the reductions were 10%, 34% and 69% from baseline in the 0.3-mg, 3-mg and 100-mg groups, compared with an 18% increase in the placebo group. Serum E2 concentrations returned to baseline within 4 days in all study subjects. A significant increase was observed in the serum concentrations of testosterone (P = 0.016), LH (P = 0.002) and FSH (P < 0.001) after administration of MPV-2213ad. Serum concentrations of cortisol and aldosterone were unaffected by MPV-2213ad. The drug was well tolerated.


CONCLUSIONS
Single oral doses of MPV-2213ad, given to healthy male subjects, induced hormonal effects typical for a specific and selective inhibitor of the aromatase enzyme. Importantly, this study design with the determination of the diurnal rhythm in the levels of the corresponding hormones gives additional validity on the results.
Ahokoski
O
O
Department of Pharmacology and Clinical Pharmacology, University of Turku, Turku University Central Hospital, Finland. outi.ahokoski@utu.fi
Irjala
K
K
Huhtala
S
S
Salminen
E
E
Scheinin
H
H
Huupponen
R
R
D000328:Adult; D047072:Aromatase Inhibitors; D001667:Binding, Competitive; D002940:Circadian Rhythm / Q000187:drug effects*; D004311:Double-Blind Method; D004562:Electrocardiography / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006439:Hemodynamics / Q000187:drug effects; D006728:Hormones / Q000097:blood*; D006801:Humans; D008297:Male; D008855:Microscopy, Electron, Scanning; D009570:Nitriles / Q000009:adverse effects / Q000494:pharmacology*; D010919:Placebos; D014230:Triazoles / Q000009:adverse effects / Q000494:pharmacology*; D016482:Urinalysis
D047072:Aromatase Inhibitors; D004791:Enzyme Inhibitors; D006728:Hormones; D009570:Nitriles; D010919:Placebos; D014230:Triazoles; C111409:finrozole