Introduction
Tamoxifen is a non-steroidal antiestrogen used to treat estrogen receptor positive breast cancers as well as prevent the incidence of breast cancer in high risk populations. Tamoxifen is used alone or as an adjuvant in these treatments. Tamoxifen may no longer be the preferred treatment for these types of cancers as patients generally have better survival, side effect profiles, and compliance with anastrozole.
Uses
Tamoxifen is a selective estrogen receptor modulator used to treat estrogen receptor positive breast cancer, reduce the risk of invasive breast cancer following surgery, or reduce the risk of breast cancer in high risk women.
Tamoxifen is indicated to treat estrogen receptor positive metastatic breast cancer in adults, as an adjuvant in the treatment of early stage estrogen receptor positive breast cancer in adults, to reduce the risk of invasive breast cancer after surgery and radiation in adult women with ductal carcinoma in situ.
Associated Conditions
Pharmacodynamics
Tamoxifen is a selective estrogen receptor modulator that inhibits growth and promotes apoptosis in estrogen receptor positive tumors. It has a long duration of action as the active metabolite N-desmethyltamoxifen has a half life of approximately 2 weeks. It has a narrow therapeutic index as higher doses can lead to breathing difficulty or convulsions. Tamoxifen administration is also associated with an increased incidence of uterine malignancies.
Mechanism of Action
Tamoxifen competitively inhibits estrogen binding to its receptor, which is critical for it's activity in breast cancer cells. Tamoxifen leads to a decrease in tumor growth factor α and insulin-like growth factor 1, and an increase in sex hormone binding globulin. The increase in sex hormon binding globulin limits the amount of freely available estradiol. These changes reduce levels of factors that stimulate tumor growth.
Tamoxifen has also been shown to induce apoptosis in estrogen receptor positive cells. This action is thought to be the result of inhibition of protein kinase C, which prevents DNA synthesis. Alternate theories for the apoptotic effect of tamoxifen comes from the approximately 3 fold increase in intracellular and mitochondrial calcium ion levels after administration or the induction of tumor growth factor β.
Absorption
An oral dose of 20mg reaches a Cmax of 40ng/mL with a Tmax of 5 hours. The metabolite N-desmethyltamoxifen reaches a Cmax of 15ng/mL. 10mg of tamoxifen orally twice daily for 3 months results in a Css of 120ng/mL and a Css of 336ng/mL.
Volume of Distribution
The volume of distribution of tamoxifen is approximately 50-60L/kg.
Protein Binding
The protein binding of tamoxifen in plasma is over 98% and mostly to serum albumin.
Route of Elimination
Tamoxifen is mainly eliminated in the feces. Animal studies have shown 75% of radiolabelled tamoxifen recovered in the feces, with negligible collection from urine. However, 1 human study showed 26.7% recovery in the urine and 24.7% in the feces.
Half Life
The terminal elimination half-life of tamoxifen is 5 to 7 days, while the half-life of N-desmethyltamoxifen, the primary circulating metabolite, is approximately 14 days.
Clearance
The clearance of tamoxifen was 189mL/min in a study of six postmenopausal women.
Toxicity
High doses of tamoxifen in animals lead to respiratory difficulty and convulsions. High doses in advanced metastatic cancer patients resulted in acute neurotoxicity seen by tremor, hyperreflexia, unsteady gait, and dizziness. Patients experiencing and overdose should be given supportive treatment as no specific treatment for overdose is suggested.
Food Interactions
- Exercise caution with St. John's Wort. This herb induces CYP3A4 metabolism, which may reduce the serum concentration of tamoxifen.
- Take with a full glass of water.
- Take with or without food.
Dosage
Anovulatory Infertility: 20mg daily on days 2, 3, 4 and 5 of cycle; if necessary the dose may be increased to 40 mg then 80 mg for subsequent courses; if cycles are irregular, start initial course on any day, with subsequent course 45 days later or on day 2 of cycle if menstruation occurs.
