Drug Interactions between etrasimod and Tamone

GENERALLY AVOID: Due to their estrogenic effect, isoflavones present in soy such as genistein and daidzein may stimulate breast tumor growth and antagonize the antiproliferative action of tamoxifen. Supportive data are derived primarily from in vitro and animal studies. In vitro, low concentrations of these phytoestrogens have been found to promote DNA synthesis and reverse the inhibitory effect of tamoxifen on estrogen-dependent breast cancer cell proliferation. In contrast, high concentrations of genistein greater than 10 microM/L have been found to enhance tamoxifen effects by inhibiting breast cancer cell growth. It is not known if these high concentrations are normally achieved in humans. Plasma concentrations below 4 microM/L have been observed in healthy volunteers given a soy diet for one month or large single doses of genistein. These concentrations are comparable to the low plasma concentrations associated with tumor stimulation reported in animals. In a study of 155 female breast cancer survivors with substantially bothersome hot flashes, a product containing 50 mg of soy isoflavones (40% to 45% genistein; 40% to 45% daidzein; 10% to 20% glycitein) taken three times a day was found to be no more effective than placebo in reducing hot flashes. No toxicity or recurrence of breast cancer was reported during the 9-week study period.

Green tea does not appear to have significant effects on the pharmacokinetics of tamoxifen or its primary active metabolite, endoxifen. In a study consisting of 14 patients who have been receiving tamoxifen treatment at a stable dose of 20 mg (n=13) or 40 mg (n=1) once daily for at least 3 months, coadministration with green tea supplements twice daily for 14 days resulted in no significant differences in the pharmacokinetics of either tamoxifen or endoxifen with respect to peak plasma concentration (Cmax), systemic exposure (AUC), and trough plasma concentration (Cmin) compared to administration of tamoxifen alone. The combination was well tolerated, with all reported adverse events categorized as mild (grade 1) and none categorized as serious or severe (grade 3 or higher) during the entire study. Although some adverse events such as headache, polyuria, gastrointestinal side effects (e.g., constipation, dyspepsia), and minor liver biochemical disturbances were reported more often during concomitant treatment with green tea, most can be attributed to the high dose of green tea used or to the caffeine in green tea. The green tea supplements used were 1000 mg in strength and contained 150 mg of epigallocatechin-3-gallate (EGCG), the most abundant and biologically active catechin in green tea. According to the investigators, the total daily dose of EGCG taken by study participants is equivalent to the amount contained in approximately 5 to 6 cups of regular green tea. However, it is not known to what extent the data from this study may be applicable to other preparations of green tea such as infusions, since the bioavailability of EGCG and other catechins may vary between preparations.

MANAGEMENT: Until more information is available, patients treated with tamoxifen may consider avoiding or limiting the consumption of soy-containing products. Consumption of green tea and green tea extracts during tamoxifen therapy appears to be safe.

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GENERALLY AVOID: Coadministration with moderate inhibitors of CYP450 3A4 such as grapefruit juice may increase the plasma concentrations of etrasimod in patients that are poor CYP450 2C9 metabolizers (e.g., *2/*3, *3/*3). Etrasimod is primarily metabolized by the CYP450 3A4, CYP450 2C8, and CYP450 2C9 isoenzymes. Pharmacokinetic studies reported that no single enzyme appears to dominate etrasimod elimination and that the involvement of multiple CYP450 isoforms reduces the likelihood of drug-drug interactions when only a single CYP450 isoform is strongly or moderately inhibited by a coadministered drug. In clinical drug interaction studies, when etrasimod was administered with the dual moderate CYP450 2C9 and 3A4 inhibitor fluconazole at steady-state levels, etrasimod systemic exposure (AUC) increased by 84%. However, concomitant use with the potent CYP450 3A4 inhibitor itraconazole increased the AUC of etrasimod by 32%, which was not considered by the manufacturer to be clinically significant. The effect on etrasimod systemic exposure in CYP450 2C9 intermediate metabolizers (e.g., *1/*2, *1/*3, *2/*2) treated with less potent CYP450 3A4 inhibitors is not known. Increased plasma concentrations of etrasimod may increase the risk of infection, bradyarrhythmia, AV conduction delays, elevated transaminase levels, and macular edema.

MANAGEMENT: Until further information is available, the consumption of grapefruit and grapefruit juice in combination with moderate to potent CYP450 2C8 inhibitors such as gemfibrozil should be avoided or limited during treatment with etrasimod in patients who are poor CYP450 2C9 metabolizers. Caution is recommended with grapefruit products consumption in patients who are intermediate CYP450 2C9 metabolizers. Patients should be advised to notify their physician if they experience potential adverse effects of etrasimod.

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