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As FDA Panel Mulls Tamoxifen Label, It Chews Role of Endoxifen, 2D6, and Rx Interactions

During a meeting last month at which a Food and Drug Administration panel debated including CYP2D6 information in a new tamoxifen label [see related story], the panel was asked to consider if the scientific evidence on the metabolism of tamoxifen demonstrates that CYP2D6 is an important pathway in the formation of endoxifen, a secondary metabolite of tamoxifen. On this, “there was no disagreement” among the panelists, according to the FDA’s meeting minutes.
In its background documents to the subcommittee, the FDA notes that endoxifen has 100-fold greater affinity for the estrogen receptor and is 30- to 100-fold more potent than tamoxifen in suppressing estrogen-dependent cell proliferation of tumor cells. This is noteworthy for patients with CYP2D6 genetic variations or those who are on CYP2D6 inhibitors, since their exposure to endoxifen is compromised.
“The enzyme CYP2D6 is a polymorphic enzyme with a number of variant alleles that are deficient or overactive in enzyme activity. Patients with deficient alleles likely have lower exposure to endoxifen and have compromised clinical effect,” the agency said in its background documents to the panel.
FDA cited several studies on the role of the CYP2D6 pathway in tamoxifen-treated patients. A study, “Exposure to Metabolites In Vivo and the role of CYP2D6,” published in the Journal of Clinical Oncology December 2005 found that in tamoxifen-treated breast cancer patients, women who lack functional CYP2D6, or carry the CYP2D6*4/*4 allele, have lower relapse-free and disease-free survival.
Data presented at the annual meeting of the American Society of Clinical Oncology in June also demonstrated that two-year relapse-free survival was 68 percent for poor CYP2D6 metabolizers and patients on strong CYP2D6 inhibitors (i.e. paroxetine or fluoxetine) versus 98 percent for those who readily metabolize CYP2D6.
However, a 226-patient study, “CYP2D6 variants and the prediction of tamoxifen response in randomized patients,” published in the Sept. 29, 2005, issue of Breast Cancer Research, found that patients with CYP2D6*4 variant allele treated with tamoxifen had a decreased recurrence rate compared to patients not treated with tamoxifen. The study concluded that the trial results contradicted their prior hypothesis and that the study needed to be confirmed in a larger cohort.
Not all panelists agreed that there was sufficient pharmacologic and clinical evidence to demonstrate that endoxifen “significantly contributes to the pharmacologic (anti-estrogenic) effect of tamoxifen.” According to the meeting minutes, the subcommittee felt that while “CYP2D6 contributed clinically to the level of endoxifen in in vitro data, there was no direct concentration or response information to indicate endoxifen is a major [emphasis retained] contributor to the clinical effect of tamoxifen,” the summary states.
Additionally, the members indicated the two issues of CYP2D6 genotyping and CYP2D6 drug interaction should be addressed separately.
“If you have a drug interaction that renders you a 2D6 poor metabolizer even if you are, genetically, an extensive metabolizer, you will not benefit from the treatment, as of course, the metabolic pathway needed for the activation of the drug is obstructed,” the head of the FDA’s Interdisciplinary Pharmacogenomics Research Group Felix Frueh explained in an e-mail. “However, there are practical considerations (i.e. compliance with drug intake, the exact type of genetic profile, etc) that make it reasonable to separate the two.”

Ultimately, the subcommittee unanimously agreed that tamoxifen’s label should be updated to include the mechanistic data, which reflects the increased risk of breast cancer for post-menopausal women with ER-positive breast cancer who are CYP2D6 poor metabolizers “by genotype or drug interaction.”

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