Tamoxifen Other names: Tamoxifen citrate

Tamoxifen citrate is an oestrogen antagonist which is believed to compete with oestrogen for binding sites in target organs. It does not have androgenic properties.

It is used as an alternative to androgens and oestrogens in the management of breast cancer in doses equivalent to 10 and 20mg of Tamoxifen twice daily by mouth.

Tamoxifen is a non-steroidal, triphenylethylene-based drug which displays a complex spectrum of oestrogen antagonist and oestrogen agonist-like pharmacological effects in different tissues. In breast cancer patients, at the tumour level, tamoxifen acts primarily as an antioestrogen, preventing oestrogen binding to the oestrogen receptor. However, clinical studies have shown some benefit in oestrogen receptor negative tumours which may indicate other mechanisms of action. In the clinical situation, it is recognised that tamoxifen leads to reductions in levels of blood total cholesterol and low density lipoproteins in postmenopausal women of the order of 10–20%. Tamoxifen does not adversely affect bone mineral density.

CYP2D6 polymorphism

CYP2D6 polymorphism status may be associated with variability in clinical response to tamoxifen. The poor metaboliser status may be associated with reduced response. The consequences of the findings for the treatment of CYP2D6 poor metabolisers have not been fully elucidated.

CYP2D6 genotype

Available clinical data suggest that patients, who are homozygote for non-functional CYP2D6 alleles, may experience reduced effect of tamoxifen in the treatment of breast cancer.

The available studies have mainly been performed in postmenopausal women.

Primary reduction of breast cancer risk

Tamoxifen reduces, but does not eliminate the risk of breast cancer. In clinical trials, tamoxifen decreased the incidence of oestrogen receptor-positive tumours, but did not alter the incidence of oestrogen receptor-negative tumours. The use of tamoxifen should be as part of a program including regular breast surveillance tailored to the individual woman, taking into account her risk of breast cancer.

Absorption

After oral administration, tamoxifen is absorbed rapidly with peak plasma concentrations of Tamoxifen occurring 4 to 7 hours after an oral dose. Steady state concentrations (about 300 ng/ml) are achieved after four weeks treatment with 40 mg daily.

Distribution

Tamoxifen is highly protein bound to serum albumin (>99%).

Biotransformation and elimination

Plasma clearance is reported to be biphasic and the terminal half-life may be longer than 7 days for tamoxifen itself, whereas that for N-desmethyltamoxifen, the principal circulating metabolite, is 14 days.

It is extensively metabolised by hydroxylation, demethylation and conjugation, the major serum metabolite being N-desmethyltamoxifen, and is excreted slowly in the faeces, mainly as conjugates. Small amounts are excreted in the urine. Tamoxifen appears to undergo enterohepatic circulation.

Paediatric population

In a clinical study where girls between 2 and 10 years with McCune Albright Syndrome (MAS) received 20 mg tamoxifen once a day for up to 12 months duration, there was an age-dependent decrease in clearance and an increase in exposure (AUC), (with values up to 50% higher in the youngest patients) compared with adults.

CYP2D6 polymorphism

Tamoxifen is metabolised mainly via CYP3A4 to N-desmethyl-tamoxifen, which is further metabolised by CYP2D6 to another active metabolite endoxifen. In patients who lack the enzyme CYP2D6 endoxifen concentrations are approximately 75% lower than in patients with normal CYP2D6 activity. Administration of strong CYP2D6 inhibitors reduces endoxifen circulating levels to a similar extent.

Tamoxifen was not mutagenic in a range of in vitro and in vivo mutagenicity tests. Tamoxifen was genotoxic in some in vitro and in vivo genotoxicity tests in rodents. Gonadal tumours in mice and liver tumours in rats receiving tamoxifen have been reported in long-term studies. The clinical relevance of these findings has not been established.

Tamoxifen is a drug on which extensive clinical experience has been obtained.