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Venlafaxine Lowers Endoxifen Levels, May Affect Tamoxifen Effectiveness

TOP - February 2013 VOL 6, NO 1

The antidepressant venlafaxine is often prescribed to patients with breast cancer who are taking tamoxifen, to help reduce the side effect of hot flashes. But according to research presented at the 2012 CTRC-AACR San Antonio Breast Cancer Symposium, venlafaxine may reduce the effectiveness of the drug.

The findings came from a multicenter prospective pharmacologic study that analyzed paired blood samples from 30 women taking venlafaxine for at least 4 weeks for the treatment of hot flashes. Blood was taken before starting venlafaxine and 8 to 16 weeks afterward. Genotyping was conducted for alleles associated with no, reduced, and ultrarapid metabolism. The aim was to examine whether venlafaxine altered the pharmacokinetics of tamoxifen and to determine the distribution of CYP2D6 genotypes in this population.

CYP2D6 is the rate-limiting enzyme responsible for the metabolic activation of tamoxifen to endoxifen. Among women taking tamoxifen, those who are extensive metabolizers of CYP2D6 have higher endoxifen concentrations, have more vasomotor symptoms, and are more likely to discontinue treatment, compared with poor metabolizers.

“The data regarding CYP2D6 genotype and cancer recurrence [have] been mixed,” said lead investigator Matthew Goetz, MD, of the Mayo Clinic in Rochester, Minnesota. “Venlafaxine is a weak CYP2D6 inhibitor not known to alter tamoxifen pharmacokinetics and is commonly recommended for tamoxifen-induced hot flashes.”

Women with tamoxifen-induced vasomotor symptoms requiring ameliorative treatment with venlafaxine were predominantly CYP2D6 extensive and ultrarapid metabolizers. Venlafaxine significantly decreased endoxifen concentrations. Across all genetic subgroups, levels were depressed by a median of about 1.6 ng/mL over time (P = .04). Limited evidence suggests that at least 6 ng/mL is needed for the prevention of breast cancer events; in the present study, 3 women with low CYP2D6 activity had levels drop below that.

Goetz acknowledged that the optimal endoxifen concentration needed for benefit is still unknown, as is the effect of venlafaxine on breast cancer outcomes. “The bottom line is that there is a decrease [in concentration]. It’s small but it’s statistically significant. The question really is, ‘Are there subgroups of patients in which this is important?’”

He concluded that “given prior data linking low endoxifen concentrations with recurrence, venlafaxine should be used with caution in tamoxifen-treated patients.”

Session moderator Hiltrud Brauch, PhD, of the Margarete Fischer-Bosch Institute of Clini-cal Pharmacology in Stuttgart, Germany, led a 2009 study showing that variations in CYP2D6 metabolism have an effect on disease-free and event-free survival in patients taking tamoxifen. “Poor metabolizers do not benefit from tamoxifen as well as extensive metabolizers,” she said. “The long and the short of it is that this matters to women.” l

Goetz MP, Suman V, Henry NL, et al. Venlafaxine inhibits the CYP2D6 mediated metabolic activation of tamoxifen: results of a prospective multicenter study: (NCT00667121). Presented at: 2012 CTRC-AACR San Antonio Breast Cancer Symposium; December 4-8, 2012; San Antonio, TX. Abstract PD10-08.

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