Arimidex Mechanism of Action





Full Prescribing Info
ATC Code: L02BG03 (Enzyme inhibitors).
Pharmacology: Pharmacodynamics: Arimidex is a potent and highly selective nonsteroidal aromatase inhibitor. In postmenopausal women, oestradiol is produced primarily from the conversion of androstenedione to oestrone through the aromatase enzyme complex in peripheral tissues. Oestrone is subsequently converted to oestradiol. Reducing circulating oestradiol levels has been shown to produce a beneficial effect in women with breast cancer. In postmenopausal women, Arimidex at a daily dose of 1 mg produced oestradiol suppression of >80% using a highly sensitive assay.
Arimidex does not possess any progestogenic, androgenic or oestrogenic activity.
Daily doses of Arimidex up to 10 mg do not have any effect on cortisol or aldosterone secretion, measured before or after standard adrenocorticotropic hormone (ACTH) challenge testing. Corticoid supplements are therefore not needed.
Primary Adjuvant Treatment of Early Breast Cancer: In a large phase III study conducted in 9366 postmenopausal women with operable breast cancer treated for 5 years, Arimidex was shown to be statistically superior to tamoxifen in disease-free survival. A greater magnitude of benefit was observed for disease-free survival in favour of Arimidex versus tamoxifen for the prospectively defined hormone receptor-positive population.
Arimidex was statistically superior to tamoxifen in time to recurrence. The difference was of greater magnitude than in disease-free survival for both the intention-to-treat (ITT) population and hormone receptor-positive population.
Arimidex was statistically superior to tamoxifen in terms of time to distant recurrence. There was also a numerical trend in favour of Arimidex for distant disease-free survival.
The incidence of contralateral breast cancer was statistically reduced for Arimidex compared to tamoxifen.
The overall survival benefit of tamoxifen was maintained with Arimidex. The additional analysis of time to death following recurrence showed a numerical trend in favour of Arimidex compared to tamoxifen.
Overall, Arimidex was well tolerated. The following adverse events were reported regardless of causality. Patients receiving Arimidex had a decrease in hot flushes, vaginal bleeding and discharge, endometrial cancer, venous thromboembolic events and ischemic cerebrovascular events compared with patients receiving tamoxifen. Patients receiving Arimidex had an increase in joint disorders (including arthritis, arthrosis and arthralgia) and fractures compared with patients receiving tamoxifen. A fracture rate of 22 per 1000 patient years was observed on Arimidex and 15 per 1000 patient years with the tamoxifen group with a median follow-up of 68 months. The fracture rate for Arimidex falls within the broad range of the fracture rates reported in an age-matched postmenopausal population.
When Arimidex and tamoxifen were co-administered, the efficacy and safety were similar to tamoxifen when given alone, irrespective of hormone receptor status. The exact mechanism of this is not yet clear. It is not believed to be due to a reduction in the degree of oestradiol suppression produced by Arimidex.
Adjuvant Treatment of Early Breast Cancer for Patients Being Treated with Adjuvant Tamoxifen: In a phase III trial (ABCSG 8) conducted in 2579 postmenopausal women with hormone receptor-positive early breast cancer being treated with adjuvant tamoxifen, patients had a superior disease-free survival when switched to Arimidex compared with those continuing on tamoxifen.
Time to any recurrence, time to local or distant recurrence and time to distant recurrence confirmed a statistical advantage for Arimidex, consistent with the results of disease-free survival. The incidence of contralateral breast cancer was very low in the 2 treatment arms, with a numerical advantage for Arimidex. Overall survival was similar for the 2 treatment groups.
Two further similar trials (GABG/ARNO 95 and ITA) with Arimidex, as well as a combined analysis of ABCSG 8 and GABG/ARNO 95, supported these results. The Arimidex safety profile in these 3 studies was consistent with the known safety profile established in postmenopausal women with hormone receptor-positive early breast cancer.
Study of Anastrozole with the Bisphosphonate Risedronate (SABRE): Bone Mineral Density (BMD): In the phase III/IV SABRE study, 234 postmenopausal women with hormone receptor-positive early breast cancer scheduled for treatment with Arimidex were stratified to low, moderate and high-risk groups according to their existing risk of fragility fracture. All patients received treatment with vitamin D and calcium. Patients in the low risk group received Arimidex alone, those in the moderate group were randomised to Arimidex plus bisphosphonate or Arimidex plus placebo and those in the high risk group received Arimidex plus bisphosphonate.
The 12-month main analysis has shown that patients already at moderate to high risk of fragility fracture had their bone health (assessed by BMD and bone formation and resorption markers) successfully managed by using Arimidex in combination with a bisphosphonate. In addition, no changes in BMD were seen in the low risk group treated with Arimidex alone and given vitamin D and calcium. These findings were mirrored in the secondary efficacy variable of change from baseline in total hip BMD at 12 months.
This study provides evidence that postmenopausal women with early breast cancer scheduled to be treated with Arimidex should have their bone status managed according to treatment guidelines already available for postmenopausal women at similar risk of fragility fracture.
Lipids: In the SABRE study, there was a neutral effect on plasma lipids both in those patients treated with Arimidex alone and in those treated with Arimidex plus a bisphosphonate.
Pediatrics: Three clinical trials were conducted in pediatric patients [2 in pubertal boys with gynecomastia and 1 in pediatric girls with McCune Albright syndrome (MAS)].
Gynecomastia Study: Trial 0006 was a randomized, double-blind, multicenter study, of 80 pubertal boys with gynecomastia of >12 months duration (aged 11-18 years inclusive) treated with Arimidex 1 mg/day or placebo daily for up to 6 months. A decrease of ≥50% in total breast volume measured by ultrasound was seen in 38.5% (15/39) of the Arimidex and 31.4% (11/35) of the placebo-treated group (odds ratio=1.513, 95% CI 0.496-4.844, p=0.4687).
Trial 0001 was an open-label, multiple-dose pharmacokinetic (PK) study of Arimidex 1 mg/day in 36 pubertal boys with gynecomastia of <12 months duration. A decrease in total breast volume of ≥50% at 6 months was seen in 55.6% (20/36) of the boys.
McCune Albright Syndrome (MAS) Study: Trial 0046 was an international, multicenter, open-label, exploratory trial of Arimidex in 28 girls (2 to ≤10 years) with MAS. No statistically significant change in the frequency of vaginal bleeding days on treatment was observed. Of the patients with baseline vaginal bleeding, 28% experienced a ≥50% reduction in the frequency of bleeding days on treatment; 40% experienced a cessation over a 6-month period and 12% experienced a cessation over a 12-month period. There were no clinically significant changes in Tanner staging, mean ovarian volume or mean uterine volume. No statistically significant change in the rate of increase in bone age on treatment compared to the rate during baseline was observed. Growth rate (in cm/year) was significantly reduced (p<0.05) from pre-treatment through month 0-12 and from pre-treatment to the second 6 months (month 7-12).
The overall assessment of the adverse events in children <18 years raised no safety and tolerability concerns.
Pharmacokinetics: Absorption of anastrozole is rapid and maximum plasma concentrations typically occur within 2 hrs of dosing (under fasted conditions). The volume of distribution in humans is 74.3 L. Anastrozole is eliminated slowly with a plasma elimination half-life of 40-50 hrs. Food slightly decreases the rate but not the extent of absorption. The small change in the rate of absorption is not expected to result in a clinically significant effect on steady-state plasma concentrations during once-daily dosing of Arimidex tablets. Approximately 90-95% of plasma anastrozole steady-state concentrations are attained after 7 daily doses. There is no evidence of time or dose dependency of anastrozole pharmacokinetic parameters.
Anastrozole pharmacokinetics is independent of age in postmenopausal women.
In boys with pubertal gynecomastia, anastrozole was rapidly absorbed, widely distributed and eliminated slowly with a half-life of approximately 2 days. PK parameters in boys were comparable to those of postmenopausal women. Clearance of anastrozole was lower in girls than in boys and exposure higher. Anastrozole in girls was widely distributed and slowly eliminated, with an estimated half-life of approximately 0.8 days.
Anastrozole is only 40% bound to plasma proteins.
Anastrozole is extensively metabolised by postmenopausal women with <10% of the dose excreted in the urine unchanged within 72 hrs of dosing. Metabolism of anastrozole occurs by N-dealkylation, hydroxylation and glucuronidation. The metabolites are excreted primarily via the urine. Triazole, a major metabolite in plasma and urine, does not inhibit aromatase.
The apparent oral clearance of anastrozole in volunteers with stable hepatic cirrhosis or renal impairment was in the range observed in healthy volunteers.
Toxicology: Preclinical Safety Data: Acute Toxicity: In acute toxicity studies in rodents, the median lethal dose of anastrozole was >100 mg/kg/day by the oral route and >50 mg/kg/day by the intraperitoneal route. In an oral acute toxicity study in the dog, the median lethal dose was >45 mg/kg/day.
Chronic Toxicity: Multiple-dose toxicity studies utilised rats and dogs. No no-effect levels were established for anastrozole in the toxicity studies, but those effects that were observed at the low dose (1 mg/kg/day) and mid-doses (dog 3 mg/kg/day; rat 5 mg/kg/day) were related to either the pharmacological or enzyme-inducing properties of anastrozole and were unaccompanied by significant toxic or degenerative changes.
Mutagenicity: Genetic toxicology studies with anastrozole show that it is not a mutagen or a clastogen.
Reproductive Toxicology: Oral administration of anastrozole to pregnant rats and rabbits caused no teratogenic effects at doses up to 1 and 0.2 mg/kg/day, respectively. Those effects that were seen (placental enlargement in rats and pregnancy failure in rabbits) were related to the pharmacology of the compound.
Oral administration of anastrozole to female rats produced a high incidence of infertility at 1 mg/kg/day and increased pre-implantation loss at 0.02 mg/kg/day. These effects were related to the pharmacology of the compound and were completely reversed after a 5-week compound withdrawal period.
The survival of litters born to rats given anastrozole at ≥0.02 mg/kg/day (from day 17 of pregnancy to day 22 postpartum) was compromised. These effects were related to the pharmacological effects of the compound on parturition. There were no adverse effects on behavior or reproductive performance of the 1st generation offspring attributable to maternal treatment with anastrozole.
Carcinogenicity: A 2-year rat oncogenicity study resulted in an increase in incidence of hepatic neoplasms and uterine stromal polyps in females and thyroid adenomas in males at the high dose (25 mg/kg/day) only. These changes occurred at a dose which represents 100-fold greater exposure than occurs at human therapeutic doses, and are considered not to be clinically relevant to the treatment of patients with anastrozole.
A 2-year mouse oncogenicity study resulted in the induction of benign ovarian tumours and a disturbance in the incidence of lymphoreticular neoplasms (fewer histiocytic sarcomas in females and more deaths as a result of lymphomas). These changes are considered to be mouse-specific effects of aromatase inhibition and not clinically relevant to the treatment of patients with anastrozole.
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