Are there any interactions between tamoxifen (Nolvadex) and sertraline (Zoloft)?/nThe question conc

Fråga: Are there any interactions between tamoxifen (Nolvadex) and sertraline (Zoloft)?

The question concerns a female patient who is treated with tamoxifen due to a breast cancer. The patient now needs treatment against anxiety and sertraline is considered as a possible choice of treatment.

Sammanfattning: Tamoxifen is metabolised via CYP2D6 to endoxifen, which is a much more potent estrogen antagonist than tamoxifen itself. Studies indicate that the clinical effect of tamoxifen could be related to the levels of endoxifen. Patients with a lower CYP2D6 metabolism (due to genetics or co-prescription of CYP2D6 inhibitors) tend to have lower levels of endoxifen in the plasma compared to extensive metabolisers. One study has shown that decreased metabolism is also related to a higher risk of recurrence and to worse survival in tamoxifen-treated breast cancer patients. Thus, the co-prescription of potent CYP2D6 inhibitors may possibly increase the risk of breast cancer relapse by inhibiting the optimal metabolic activation of tamoxifen.

Sertraline is only a moderate inhibitor of CYP2D6. The clinical relevance of co-prescription of sertraline during tamoxifen-treatment is unclear.

Svar: No studies have been found that concerns interactions between tamoxifen and sertraline specifically. However, sertraline have been used as one of many different CYP2D6-inhibitors in some of the studies with tamoxifen referred to below.

Tamoxifen is an antiestrogen substance that is used as palliative and adjuvant treatment of estrogen-receptor-positive breastcancer (1). Tamoxifen is metabolised to 4-hydroxy-tamoxifen and N-desmethyl-tamoxifen (NDM) mainly by CYP3A, and to 4-hydroxy-N-desmethyl-tamoxifen (endoxifen) by CYP2D6 (2). In vitro studies have shown that endoxifen and 4-hydroxy-tamoxifen are approximately 100 times more potent than tamoxifen as antiestrogen antagonists. Endoxifen is present at notably higher concentrations than 4-hydroxy-tamoxifen in the plasma of breast cancer patients receiving chronic tamoxifen therapy (3). According to the measured plasma-concentrations of tamoxifen and endoxifen in the studies below, the level of the endoxifen-concentration seems to be around 20% of that of tamoxifen.

The clinical effects of tamoxifen with respect to efficacy and toxicity vary widely among individuals. The mechanisms for this variable response have been unclear. Earlier studies have shown that the level of the plasma concentration of tamoxifen is not related to the clinical outcome. This has lead to the hypothesis that altered patterns of metabolism of tamoxifen might contribute to interindividual variability in effects (3). As endoxifen is present in higher concentrations than 4-hydroxy-tamoxifen in the plasma, endoxifen is likely to have an important impact on the outcome of the treatment. The plasma levels of endoxifen have therefore been studied in relation to CYP2D6 activity.

Sertraline (a selective serotonin uptake inhibitor) is a moderate inhibitor of CYP2D6 (4). Three different studies have shown that the plasma concentrations of endoxifen is lower in patients who are also co-prescribed medications with CYP2D6 inhibitors, and that the reduction is related to the amount of inhibition (3, 5, 6)

In one study, the plasma concentrations of tamoxifen and its metabolites where measured in 158 female breast cancer patients who were treated with tamoxifen (20 mg/day). 46 of these patients were also prescribed medication with a CYP2D6 inhibitor. After 4 months of tamoxifen treatment, the plasma concentration of endoxifen was significantly lower in patients who also received a CYP2D6 inhibitor than in these who were not (39.6 +/-28.4 nmol/L versus 71.5+/-41.2 nmol/L). The decrease was more pronounced in patients who were treated with potent CYP2D6 inhibitors than in those who received weak CYP2D6 inhibitor (24.6+/-16.6 nmol/L versus 50.1+/-30.4 nmol/L). There was no significant difference in mean plasma concentrations of tamoxifen, NDM or 4-hydroxytamoxifen (5).

In another study, the plasma concentrations of tamoxifen and its metabolites where measured in 78 breast cancer patients treated with 20 mg tamoxifen/day. 24 of these were also on medication with a CYP2D6 inhibitor. Also in this study, the plasma concentration of endoxifen was significantly lower in the subjects who were receiving treatment with a CYP2D6 inhibitor. The reduction was also correlated to the patients CYP2D6 genotype, with a greater reduction (58%) of mean plasma concentration of endoxifen in subjects who carried the Wt/Wt genotype and were treated with CYP2D6 inhibitors, compared to a 38% reduction in subjects who were heterozygous for a non-functional CYP2D6 allele and received treatment with a CYP2D6 inhibitor. The plasma endoxifen concentration was slightly reduced in women prescribed venlafaxine (a week inhibitor of CYP2D6), whereas the plasma endoxifen concentration was reduced substantially in subjects who received paroxetine (a potent inhibitor of CYP2D6) (3).

In a third study, tamoxifen and its metabolites were measured in plasma before and after 4 weeks with co-administered paroxetine in 12 women with tamoxifen-treated breast cancer. Co-administration of paroxetine clearly decreased the endoxifen concentrations, from a mean of 12.4 ng/mL before paroxetine coadministration to 5.5 ng/mL afterward. The reduction was more pronounced in the patients with a wild type CYP2D6 genotype than in these with a variant CYP2D6 allele (*4, *6, or *8), who had lower baseline plasma endoxifen concentrations. Paroxetine had no statistically significant effect on endoxifen levels in women who were homozygous carriers of variant alleles (6).

In a study of 256 tamoxifen-treated breastcancer patients, the CYP2D6 genotype and the co-medication with CYP2D6 inhibitors could be determined in 171 of the 256 patients. The patients were thereafter divided into groups according to their metabolizer status extensive, intermediate or poor metabolizers. Patients with decreased metabolism had significantly shorter TTBR (time to breast cancer recurrence, HR=1.91), RFS (relapse-free survival, HR=1.74) and DFS (disease-free survival, HR=1.60) than patients with extensive metabolizer status. The poor metabolizers also tended to have worse OS (overall survival) compared to patients with extensive CYP2D6 metabolism. By classifying patients according to the extent in which CYP2D6 enzyme activity was reduced, it was also demonstrated that the effect of the reduced metabolism appeared greatest in poor metabolizers, who had a greater than threefold higher risk of recurrence compared to extensive metabolisers (7).