Anastrozole

Pharmacological properties

Anastrozole is a potent, highly selective non-steroidal aromatase inhibitor. in postmenopausal women, estradiol is produced primarily by converting androstenedione to estrone using the aromatase enzyme in peripheral tissues. estrone is further converted to estradiol.

A decrease in estradiol levels has a therapeutic effect in women with breast cancer. In postmenopausal women, taking anastrozole in a daily dose of 1 mg leads to a decrease in estradiol by 80%.

Anastrozole does not have progestogen and androgenic activity; in daily doses up to 10 mg does not affect the secretion of cortisol and aldosterone, measured before and after the standard ACTH stimulation test. Thus, there is no need for corticosteroid replacement administration.

Clinical Efficiency and Safety

Common breast cancer

Line I therapy for postmenopausal women with advanced breast cancer. In clinical studies, the effectiveness of anastrozole at a dose of 1 mg and tamoxifen (a line I preparation for the treatment of locally advanced or metastatic breast cancer with positive or unknown hormone receptor values ​​in postmenopausal women) was evaluated at a dose of 20 mg once a day. The main end result was tumor progression time, tumor objective response rate, and safety.

Evaluation of the main end indicators showed that anastrozole had a statistically significant advantage over tamoxifen in terms of tumor progression (median progression time of 11.1 and 5.6 months for anastrozole and tamoxifen, respectively); the frequency of the objective response of the tumor was the same for both drugs.

Another study showed that the frequency of the objective response of the tumor and the time of tumor progression for anastrozole and tamoxifen were similar. Evaluation of secondary endpoints confirmed the level of major endpoint performance indicators. The rather low mortality rate in the treatment groups of both studies did not allow to draw conclusions about the differences in overall survival rates.

Line II therapy for postmenopausal women with advanced breast cancer. Anastrozole in doses of 1 mg or 10 mg once a day and megestrol acetate at a dose of 40 mg 4 times a day was studied in two controlled clinical trials involving postmenopausal women with advanced breast cancer, in which the disease progressed after treatment with tamoxifen for advanced breast cancer gland or breast cancer at an early stage. The time of progression and the frequency of an objective response were the main indicators of effectiveness. The incidence of prolonged (24 weeks) stable disease, the rate of progression, and overall survival were also determined. In both studies, there were no significant differences between treatment groups for any of the efficacy parameters.

Mineral bone density. In phase III / IV studies of postmenopausal women with early breast cancer with positive hormone receptor levels who were planning to administer anastrozole at a dose of 1 mg / day, they were divided into groups with low, medium and high risk in accordance with their risk of occurrence osteoporotic fracture. The main efficiency parameter was an analysis of bone density of the lumbar spine using dual-energy scanning by X-ray absorptiometry. All patients received vitamin D and calcium. Patients in the low-risk group received only anastrozole; patients in the middle-risk group received anastrozole and risedronate at a dose of 35 mg once a week or anastrozole and placebo; patients in the high-risk group received anastrozole and risedronate at a dose of 35 mg once a week. The main final indicator was a change in bone density of the lumbar spine after 12 months compared with the initial level.

An updated analysis after 12 months showed that in patients with an average and high risk of osteoporotic fracture, there was no decrease in bone density when treated with anastrozole at a dose of 1 mg / day in combination with risedronate at a dose of 35 mg once a week. In addition, a decrease in bone mineral density, which was not statistically significant, was recorded in the low-risk group when treated with anastrozole alone at a dose of 1 mg / day. These results were reflected in an additional variable efficiency, a change in the total mineral density of the femur bones after 12 months compared with the initial level.

This study proves that it is advisable to consider the use of bisphosphonates in case of possible bone loss in postmenopausal women with breast cancer in the early stages, which are scheduled for the appointment of anastrozole.

Pharmacokinetics Suction. Anastrozole absorption fast, C_max in blood plasma is reached within 2 hours after administration (on an empty stomach). Food somewhat slows down the rate, but not the degree of absorption. Minor changes in the rate of absorption do not lead to a clinically significant effect on the equilibrium concentration in the blood plasma when using anastrozole 1 time per day. Approximately 90–95% of the equilibrium concentration of anastrozole in blood plasma is reached after 7 days of using the drug, the accumulation is 3-4 times. There is no information on the dependence of the pharmacokinetic parameters of anastrozole on time or dose.

The pharmacokinetics of anastrozole does not depend on the age of postmenopausal women.

Distribution. Only 40% of anastrozole binds to plasma proteins.

Metabolism and excretion. Anastrozole is extensively metabolized in postmenopausal women, less than 10% of the dose is excreted unchanged in the urine within 72 hours after administration. Anastrozole is excreted slowly, T_½ 40–50 hours. Anastrozole metabolism is carried out by N-dealkylation, hydroxylation and glucuronidation. Metabolites are excreted mainly in urine. Triazole, a major plasma metabolite, does not inhibit aromatase.

Impaired renal or hepatic function. The concentration of anastrozole in the blood plasma of volunteers with cirrhosis was within the range of concentrations found in healthy subjects.

The plasma anastrozole concentration, which was observed during long-term efficacy studies in patients with impaired renal function, was within the range of plasma anastrozole concentrations observed in patients without impaired renal function. The use of anastrozole in patients with severe renal impairment requires caution.

Indications

Treatment of common breast cancer with positive hormone receptor counts in postmenopausal women.

Application

Take the drug orally. The recommended dose for adults, including older women, is 1 tablet (1 mg) once a day.

In invasive breast cancer with positive hormone receptor levels in the early stages of postmenopausal women, the recommended duration of adjuvant endocrine therapy is 5 years.

Renal failure. Patients with mild or moderate impaired renal function do not require dose adjustment. The use of the drug in this group of patients requires caution.

Liver failure. Patients with mild liver disease do not require dose adjustment. The use of the drug in this group of patients requires caution.

Children. Anastrozole is not recommended for children due to insufficient safety and efficacy data.

Contraindications

Known hypersensitivity to anastrozole or any component of the drug; During pregnancy and breastfeeding.

Side effects

In the table.1 presents adverse reactions identified during clinical and post-registration studies or received in the form of spontaneous messages. unless otherwise indicated, frequency categories were calculated based on the number of adverse events observed in a phase III trial involving postmenopausal women with operable breast cancer who received adjuvant therapy for 5 years.

The following adverse reactions are distributed by frequency and organ system classes. The frequency distribution was carried out according to the following criteria: very often (≥1 / 10), often (≥1 / 100, 1/10), infrequently (≥1 / 1000, 1/100), rarely (≥1 / 10,000, 1 / 1000) and very rarely (1/10 000). The most commonly reported adverse reactions include headache, hot flashes, nausea, rashes, arthralgia, impaired joint mobility, arthritis and asthenia.

* The incidence of carpal tunnel syndrome was greater in patients who received anastrozole during clinical trials than in patients who received tamoxifen. However, most of these cases occurred.