Anastrozole Sandoz Mechanism of Action

Pharmacotherapeutic Group: Enzyme inhibitors. ATC Code: L02BG03.
Pharmacology: Pharmacodynamics: Mechanism of Action and Pharmacodynamic Effects: Anastrozole is a potent and highly selective non-steroidal aromatase inhibitor. In postmenopausal women, estradiol is produced primarily from the conversion of androstenedione to estrone through the aromatase enzyme complex in peripheral tissues. Estrone is subsequently converted to estradiol. Reducing circulating estradiol levels has been shown to produce a beneficial effect in women with breast cancer. In postmenopausal women, anastrozole at a daily dose of 1 mg produced estradiol suppression of greater than 80% using a highly sensitive assay.
Anastrozole does not possess any progestogenic, androgenic, or estrogenic activity.
Daily doses of anastrozole up to 10 mg do not have any effect on cortisol or aldosterone secretion, measured before or after standard adrenocorticotrophic hormone (ACTH) challenge testing. Corticoid supplements are therefore not needed.
Pharmacokinetics: Absorption: Absorption of anastrozole is rapid and maximum plasma concentrations typically occur within two hours of dosing (under fasted conditions). 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 anastrozole tablets. Plasma anastrozole steady-state concentrations are attained after 7 daily doses, and accumulation is 3- to 4-fold.
Distribution: Anastrozole is only 40% bound to plasma proteins.
Elimination: Anastrozole is eliminated slowly with a plasma elimination half-life of 50 hours. Anastrozole is extensively metabolized in the liver. Hepatic metabolism accounts for about 85% of the elimination of anastrozole, with renal excretion accounting for only 10% of total clearance. Metabolism of anastrozole occurs by N-dealkylation, hydroxylation and glucuronidation. The metabolites are excreted primarily via the urine. Triazole, the major metabolite in plasma, does not inhibit aromatase.
Renal or hepatic impairment: The apparent oral clearance of anastrozole was reduced by approximately 30% in individuals with stable hepatic cirrhosis related to alcohol abuse compared with controls with normal hepatic function. However, plasma anastrozole concentrations observed in individuals with hepatic cirrhosis were within the range of concentrations observed in normal individuals across all clinical trials.
Although the renal clearance of anastrozole decrease proportionally with creatinine clearance and is reduced by about 50% in individuals with severe renal impairment (cleatinine clearance less than 30 ml/minute per 1.73 m²) compared with controls, total body clearance of anastrozole is reduced by only 10% in patients with severe renal impairment.
Paediatric population: Following 1 mg once daily multiple administration in children, the mean T_max was 1 hour. The mean (range) disposition parameters of anastrozole in children were described by a CL/F of 1.54 L/h (0.77 to 4.53 L/h) and apparent volume of distribution (V/F) of 98.4 L (50.7 to 330 L). The terminal elimination half-life was 46.8 hours, which was similar to that observed in postmenopausal women treated with anastrozole for breast cancer. Based on a population pharmacokinetic analysis, the pharmacokinetic of anastrozole were similar in boys with pubertal gynecomastia and girls with McCune Albright Syndrome.
Toxicology: Preclinical Safety Data: Reproductive toxicology: Anastrozole has been shown to cross the placenta in rats and rabbits receiving oral doses of 0.1 mg/kg (approximately 1 and 1.9 times the recommended human dose, respectively, on a mg/m² basis). Increased pregnancy loss was demonstrated in rats and rabbits receiving anastrozole dosages equal to or exceeding 0.1 and 0.02 mg/kg daily, respectively (about one and one-third times the recommended human dosage, respectively, on a mg/m² basis), during the period of organo genesis; in rats, this effects was dose-related.
Impairment of fertility and effects on the reproductive organ associated with anastrozole in female rats.