Drug interactions involving CYP2D6, genetic variants, and variability in clinical response
Article date: November 2010
Tamoxifen is a selective oestrogen-receptor modulator indicated for palliative and adjuvant treatment of oestrogen-receptor-positive breast cancer in premenopausal and postmenopausal women. Tamoxifen is a prodrug, and the formation of the active metabolite, endoxifen, is mediated by the CYP2D6 enzyme. Several articles have recently been published regarding the potential effect of CYP2D6 genetic variants on clinical response to tamoxifen treatment in patients with breast cancer.
In patients with inherited non-functional alleles of the CYP2D6 gene (‘poor metabolisers’) or in patients concomitantly treated with CYP2D6 enzyme inhibitors, concentrations of the tamoxifen metabolites that most strongly bind to the oestrogen receptor may be reduced.
Effect of tamoxifen in patients treated with potent CYP2D6 inhibitors
A population-based cohort study on SSRI antidepressants and breast-cancer mortality in women receiving tamoxifen found that the risk of death from breast cancer increased with the length of concomitant treatment with paroxetine—a potent inhibitor of CYP2D6, but not with other SSRIs. The proportion of time on tamoxifen with overlapping use of paroxetine of 25%, 50%, and 75% was associated with 24%, 54%, and 91% increases in the risk of death from breast cancer, respectively.1
A more-recent study2 found no evidence for decreased efficacy with the co-administration of CYP2D6 inhibitors and tamoxifen, but given the strong mechanistic model and overall weight of evidence it is recommended that strong CYP2D6 inhibitors should be avoided whenever possible in patients taking tamoxifen. Examples of such drugs include:
Association of CYP2D6 polymorphism status with poor clinical outcome
The evidence linking various poor metaboliser genotypes and tamoxifen treatment outcomes is mixed and inconclusive. Therefore there is no current recommendation for genetic testing before treatment with tamoxifen.3 4 5 6 7 8 9 10 11 12
Advice for healthcare professionals:
- concomitant use of drugs that are potent inhibitors of the CYP2D6 enzyme should be avoided whenever possible in patients treated with tamoxifen for breast cancer
- current data for the effect of genetic polymorphisms are insufficient to support recommending genotyping of patients
Further information is available in a report from the September 2010 meeting of the European Pharmacovigilance Working Party.
Article citation: Drug Safety Update Nov 2010 vol 4, issue 4: A1.
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