Drug Interaction Report

GENERALLY AVOID: Theoretically, high levels of dehydroepiandrosterone (also known as prasterone or DHEA) may negate the pharmacologic effects of selective estrogen receptor modulators (SERMs) like tamoxifen and estrogen receptor antagonists like fulvestrant when they are used to treat estrogen receptor positive cancer. In vitro studies have demonstrated that the sulfate conjugate of DHEA (DHEA-S) is estrogenic in a low-estrogen environment, allowing it to compete with SERMs and estrogen receptor antagonists to bind to the estrogen receptor and promote cell growth in estrogen receptor positive breast cancer cells. The in vitro study that analyzed this potential interaction with tamoxifen found that tamoxifen's ability to inhibit cell growth could be circumvented by DHEA-S at concentrations >= 90 mcg/dL; while the study analyzing DHEA-S with fulvestrant used a concentration of 900 mcg/dL.

MANAGEMENT: The use of dehydroepiandrosterone (also known as prasterone or DHEA) should be generally avoided in patients using SERMs like tamoxifen or estrogen receptor antagonists like fulvestrant. Some authorities consider the use of DHEA to be contraindicated in patients with a known or suspected estrogen dependent tumor as well as in patients with a known or suspected history of breast cancer. Consultation with an oncologist as well as a gynecologist should be considered prior to starting this combination.

GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of elacestrant, which is primarily metabolized by CYP450 3A4. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. Inhibition of hepatic CYP450 3A4 may also contribute. The interaction has not been studied with grapefruit juice but has been reported for other CYP450 3A4 inhibitors. When elacestrant (172 mg once daily) was administered with itraconazole, a potent CYP450 3A4 inhibitor, elacestrant peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 4.4-fold and 5.3-fold, respectively. Concomitant use of fluconazole, a moderate CYP450 3A4 inhibitor, is predicted to increase elacestrant (345 mg single dose) Cmax and AUC by 1.6-fold and 2.3-fold, respectively. In general, the effect of grapefruit juice is concentration-, dose- and preparation-dependent, and can vary widely among brands. Certain preparations of grapefruit juice (e.g., high dose, double strength) have sometimes demonstrated potent inhibition of CYP450 3A4, while other preparations (e.g., low dose, single strength) have typically demonstrated moderate inhibition. Increased exposure to elacestrant may increase the risk of adverse reactions such as musculoskeletal pain, nausea, dyslipidemia, increased liver enzymes, fatigue, decreased hemoglobin, and vomiting.

Administration of elacestrant (345 mg) with a high-fat meal (800 to 1000 calories, 50% fat) increased elacestrant Cmax and AUC by 42% and 22%, respectively, compared to fasted conditions.

MANAGEMENT: It may be advisable for patients to avoid consumption of grapefruit, grapefruit juice, or supplements that contain grapefruit during treatment with elacestrant. Elacestrant should be taken with food at approximately the same time each day.