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The Clinical Pharmacology of Anastrozole

Clinical Pharmacology of Anastrozole Mechanism of Action

Anastrozole is a potent non-steroidal AI, also called a type II AI. AIs are divided into two types based on the method by which aromatase is inhibited. Type I AI drugs are steroidal, and the only type I drug currently available is exemestane. Type I AIs bind irreversibly to aromatase and cause permanent inactivation. Type II AIs are non-steroidal. Anastrozole and letrozole are the currently available type II drugs. Type II AIs bind reversibly to aromatase by competing with the endogenous ligands for the active site of aromatase. They do this by forming a reversible bond to the haem iron atom in the active site.22

Standard Dose

The standard dose of anastrozole is 1mg/day – this dose recommendation resulted from two dose-finding studies conducted in healthy post-menopausal women.23

In one study, volunteers took

3mg anastrozole daily for 10 days and in the other study volunteers took either 0.5 or 1mg anastrozole daily for 14 days. This was done to assess both the pharmacokinetics of anastrozole and the oestrogen-lowering effect of anastrozole. All three doses resulted in >80% reduction of oestradiol concentrations for up to 144 hours after the last dose of anastrozole. Further comparison of volunteers with oestradiol concentrations below the detection limit suggested that 1mg daily is required to achieve the maximal oestrogen suppression. In addition, serum concentrations of gonadotrophins or adrenal steroids were not affected by anastrozole administration.23

Another two studies comparing the effect of 1 versus 10mg/day anastrozole with megestrol acetate 40mg four times daily on post-menopausal women with advanced breast cancer showed that the 10mg dose of anastrozole did not result in greater clinical benefit.24,25

As a result of these studies, anastrozole 1mg/day became the recommended therapeutic dose.


Animal studies with radio-labelled anastrozole have shown that anastrozole has good bioavailability when administered orally.26


human study later confirmed that it takes two to three hours after oral administration for anastrozole to reach maximal concentration.23


Once absorbed, anastrozole is widely distributed throughout the body, with about 40% being bound to plasma proteins.27 The pharmacokinetics of anastrozole is linear and does not change with repeated dosing.28

intake does not significantly affect steady-state serum concentration of the drug.22

The other two metabolites are a glucuronide conjugate of hydroxyanastrozole and a glucuronide of anastrozole itself. Anastrozole is primarily excreted through the faecal route. As hepatic metabolism accounts for 85% of anastrozole elimination, anastrozole pharmacokinetics have been studied in patients with liver cirrhosis resulting from alcohol abuse. Compared with subjects with normal hepatic function, the oral clearance of anastrozole in patients with stable liver cirrhosis was 30% lower. The plasma concentration of anastrozole was, however, in the same range as that observed in subjects with normal hepatic function. As a result, there is no dose adjustment required in patients with stable hepatic insufficiency.28

Anastrozole is extensively metabolised in the liver through N-dealkylation, hydroxylation and glucuronidation to produce three major metabolites, which account for 95% of the metabolites created.27 Triazole is the major circulating metabolite of anastrozole and it is inactive.28


About 10% of the anastrozole dose is excreted unchanged in the urine. Sixty per cent is excreted as metabolites in the urine.28

As a

result, anastrozole pharmacokinetics do not change significantly in patients with renal impairment, as defined by creatinine clearance less than 30ml/minute/1.73m2. Dose adjustment in patients with renal insufficiency is not necessary.28


Anastrozle is a highly selective AI as it significantly suppresses serum oestrogen metabolite (oestrone, oestradiol and oestrone sulphate) concentration without significantly affecting the concentrations of corticosteroids and other hormones, such as gonadotrophins or adrenal steroids.23

Aromatase inhibition is primarily achieved by

anastrozole as a prodrug. Anastrozole suppresses plasma oestrone (E1) concentration by 81–87%, oestradiol (E2) by 84–85% and oestrone sulphate (E1S) by 94%.29

Drug–Drug Interactions

Anastrozole is extensively metabolised in the liver. However, the metabolic pathway has not been elucidated. In vitro studies demonstrated that anastrozole inhibited CYP1A2, CYP2C8/9 and CYP3A4 (with magnitudes in descending order) at concentrations unlikely to be achieved at therapeutic doses, but had no effect on CYP2A6 or CYP2D6.30

Clinically significant drug–drug interactions are

therefore unlikely but may occur if the patient is taking medicines that interact with the cytochrome P450 system.

The ATAC trial included a third arm of combined tamoxifen and anastrozole. This combination was not better than tamoxifen alone, but was inferior to anastrozole alone. A substudy of the ATAC trial showed that concurrent administration of anastrozole and tamoxifen lowered the concentration of anastrozole by 27% (90% confidence interval 20– 33%; p<0.001). This was despite the fact that anastrozole suppression did not correlate with systemic oestradiol suppression.31

In addition, the

authors’ group recently showed that simvastatin is unlikely to alter the pharmacokinetics of anastrozole in a clinically meaningful way.32

It was

found that 14-day treatment with simvastatin had no statistically significant effect on the plasma concentrations of anastrozole (median difference -4.2 [-22.1, 6.2]; p=0.36) and hydroxyanastrozole (median difference 0.03 [-0.08, 0.14]; p=0.73). Moreover, 14-day concomitant administration of simvastatin had no statistically significant effect on the plasma concentrations of oestradiol or oestrone sulphate (median difference 3.0 [-9.5, 19.0]; p=0.27).32

A number of studies have

investigated the drug–drug interactions between anastrozole and a few other drugs and showed little evidence of significant drug–drug interactions. In 2001, Yates et al. published a randomised, double-blind, placebo-controlled, single-centre trial on 16 healthy male volunteers who were randomised to receive either 11 days of anastrozole followed by placebo or placebo followed by anastrozole. All subjects received 25mg warfarin on day three of each treatment session. Comparing the pharmacokinetic data from both arms showed that anastrozole did not change the pharmacokinetics of warfarin. Nor did it change the pharmacodynamic feature of warfarin by affecting prothrombin time, thrombin time, activated partial thromboplastin time and factor VII.33

In 2003, Repetto et al. reported a 10-patient study evaluating the pharmacokinetic interaction between anastrozole and quinapril in elderly patients with breast cancer and hypertension. Patients were divided into two groups: one group treated with anastrozole for over 10 weeks and the other group treated with anastrozole for 10


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