[Introduction of a new aromatase inhibitor fadrozole hydrochloride hydsate].

Fadrozole (CGS 16949 A, brand name: Afema) is an aromatase inhibitor developed firstly in Japan. This compound reduces estrogen levels in the body after administration, suppressing the growth of breast cancer. In animal experiments, this showed an inhibitory activity in vivo against estrogen-depended mammary tumor and the effect was potentiated by the combination of tamoxifen cytrate. In the domestic clinical trials against post-menopausal advanced-recurrent breast cancer, irrespective of the cases with ER positive or negative and even including pretreated cases, the compound showed response rate of 19.3%, the rate of long NC of 18.2%, and the total response rate of 37.5%. The prognosis of NC cases was similar to the effective (CR + PR) cases. The median survival time was 323.5 days which were better than the previous endocrine therapies. The side effects mainly consisted of nausea, vomiting, loss of appetite, abdominal pain, and fatigue, but these were all the level of grade 1. This compound-seemed to be a promising drug for the treatment of patients with post-menopausal breast cancer.

[Phase I study of CGS16949A--a new aromatase inhibitor. Cooperative Study Group for CGS16949A].

Phase I study of CGS16949A--a new aromatase inhibitor--was performed in postmenopausal women with advanced breast cancer who received either single oral administration of 4 and 8 mg, or multiple oral daily administration of 1, 2, 4, 8 and 16 mg for 5.5 days. No side effects were observed after single dose administration of 4 mg and 8 mg of CGS16949A. In the multiple administration, one patient received 1 mg/day for 3 days complained of abdominal pain (Grade 2), but administration of CGS16949 A was continued despite of the pain. In order to assess the causal relationship of the drug with the abdominal pain, the number of patients in 1 mg/day group was doubled from 3 to 6 patients, but no side effects were observed in the remaining five patients. In addition, no side effects, including abdominal pain, were noted in the other 2, 4, 8 and 16 mg/day groups. After multiple administration, plasma concentrations of estradiol at 5 hrs after the final dosage in the respective dose groups were reduced to 47.1 +/- 8.3%, 37.3 +/- 3.0%, 28.0 +/- 7.8%, 26.0 +/- 11.3% and 26.6 +/- 13.8% respectively. Similar tendencies were observed in estrone plasma levels and urinary estrogens levels. In this study, the reduction of plasma estrogen levels was confirmed following administration of CGS 16949A. The clinical usefulness of this new aromatase inhibitor remains to be studied further.

Dose proportionality and population characteristics of oral fadrozole hydrochloride, an aromatase inhibitor, in postmenopausal women.

The dose proportionality of the pharmacokinetics of fadrozole was investigated in 18 healthy postmenopausal women. Fadrozole hydrochloride was administered as 0.3-, 1.0-, and 2.0-mg oral doses continuously every 12 hr for 5 days each in a Latin square design. At steady state, the dose-normalized pharmacokinetic parameters AUC and Cmax were found to be independent of the dose. In addition, no statistically significant differences in tmax were detected. It was concluded that the pharmacokinetics of fadrozole were dose proportional in the projected therapeutic dose range. The relationship between oral clearance and the demographic factors, age, weight, and height, was assessed. Oral clearance was related to total body weight but not age or height. Prospective estimates of the population components of variance showed that intersubject variance accounted for 91.7% of the total random variance. Weight variance accounted for 36.1% of the intersubject variance.

The effect of food on the relative bioavailability of fadrozole hydrochloride.

The effect of food on the pharmacokinetic disposition of fadrozole hydrochloride was evaluated in nine healthy male and female volunteers. Single 12 mg doses of fadrozole were orally administered to subjects immediately following a standardized meal or after fasting for 12 h, in a randomized crossover design. No statistically significant treatment differences were detected for the pharmacokinetic parameters AUC and half-life. Cmax was significantly reduced by 15% for the fed treatment relative to the fasted treatment, and tmax was delayed by 39%. These findings indicate that the concomitant ingestion of food with fadrozole delays the gastric emptying and/or absorption of fadrozole, but has no effect on the extent of absorption.

Effects of the nonsteroidal aromatase inhibitor, fadrozole, on the sexual behavior of male cynomolgus monkeys (Macaca fascicularis).

In many vertebrates, castration and hormone replacement and, more recently, the use of aromatase inhibitors, have shown that male sexual activity is mediated by the aromatization of testosterone (T) to estradiol (E2). In macaques, however, the systemic administration of E2, either alone or in combination with androgen, failed either to maintain or to restore the sexual activity of castrated males. The present study examines the effects of administering the nonsteroidal aromatase inhibitor, Fadrozole, either alone or combined with E2, to castrated, T-treated male cynomolgus monkeys at a dose of 0.25 mg/kg/day. This dose inhibited by over 98% the conversion of T to E2 and the subsequent accumulation of the latter in hypothalamic cell nuclei. Castrated males bearing sc Silastic impants of T were each tested with an ovariectomized, E2-treated female partner before, during, and after being given minipumps delivering either Fadrozole or water (240 1-hr tests). Within 2 weeks, Fadrozole significantly reduced ejaculatory activity and male sexual motivation in the absence of changes in plasma T levels, which remained in the upper range for intact males. Additional estradiol treatment produced small but significant increases in ejaculations by three of the six males only, and measures of male sexual motivation remained unchanged (120 tests). The present results, which stand in contrast to our previous findings in macaques, support the view that aromatization of T is important for ejaculatory activity and sexual motivation in a male primate. They also suggest that exogenous E2, which reaches the brain from the systemic circulation, does not fully duplicate the behavioral effects of E2 produced locally in the brain by the aromatization of T.