Grapefruit - Xpovio (Selinexor) Interaction

Interaction Details

Selinexor is classified as belonging to the following category: Cytochrome P450 3A4 (Cyp3A4) Substrates

Grapefruit juice can increase levels of drugs metabolized by CYP3A4.
Clinical research shows that grapefruit juice can inhibit CYP3A4 metabolism of drugs, causing increased drug levels and potentially increasing the risk of adverse effects. When taken orally, effects of grapefruit juice on CYP3A4 levels appear to last at least 48 hours. Grapefruit's ability to inhibit CYP3A4 has even been harnessed to intentionally increase levels of venetoclax, which is metabolized by CYP3A4, in an elderly patient with acute myeloid leukemia who could not afford full dose venetoclax. The lower dose of venetoclax in combination with grapefruit juice resulted in serum levels of venetoclax in the therapeutic reference range of full dose venetoclax and positive treatment outcomes for the patient.
Professional consensus recommends the consideration of patient age, existing medical conditions, additional medications, and the potential for additive adverse effects when evaluating the risks of concomitant use of grapefruit juice with any medication metabolized by CYP3A4. While all patients are at risk for interactions with grapefruit juice consumption, patients older than 70 years of age and those taking multiple medications are at the greatest risk for a serious or fatal interaction with grapefruit juice.

Interaction Rating

Likelihood of Occurrence

Well-controlled human studies have demonstrated the likely existence of this interaction

Pharmacist Analysis

This interaction is theoretical based on studies showing that grapefruit can inhibit certain CYP metabolizing enzymes.

However, while CYP3A was shown to be a possible elimination pathway of Xpovio (selinexor) in experiments, a drug-drug-interaction (DDI) study with clarithromycin, a known CYP3A inhibitor, demonstrated no clinically significant differences in Xpovio (selinexor) pharmacokinetics.

The study showed concentrations of Xpovio (selinexor) in the blood increased slightly, but it was not considered a big enough change to be clinically significant. Since the approval of selinexor, there have been no reports of any serious problems or interactions with any other drugs.

A more in-depth look at the study is summarized in the bullet points below:

• The drug-drug interaction (DDI) study was nested in a Phase 1b/2 study, in which the DDI portion consisted of a 14-day PK Run-in phase, where selinexor 40 mg was administered alone on Day 1, clarithromycin 500 mg BID was administered on Days 2-8, and selinexor 40 mg was again administered on Day 8 with the morning clarithromycin dose.


• Results showed similar plasma PK profiles for selinexor when administered alone and when co-administered with clarithromycin.


• The 90% CI of the geometric least square mean ratio (GLSMR) for selinexor when administered in combination with clarithromycin vs selinexor alone for AUC0-t and AUC0-inf was 0.99 (0.90, 1.08) and 1.00 (0.92, 1.08), respectively, which are within the no effect boundary of 0.8-1.25. This indicates that the apparent clearance of selinexor is not affected by strong CYP3A inhibition. Co-administration with clarithromycin increased the Cmax of selinexor by 17% (90% CI of 3 to 34%). This increase in Cmax was small and was considered to be clinically not relevant.


• Since the approval of selinexor, no reports of clinically significant interactions of selinexor with any known CYP3A inducer or inhibitor have been received in clinical studies or in post-marketing surveillance.

Resources for this analysis:

• A Phase 1b/2, Open-label, Two-period, Sequential Study to Assess the Effects of Clarithromycin on the Pharmacokinetics of Selinexor in Patients With Multiple Myeloma. ACCP.
• Personal communication with 'Global Medical Information Associate Director' - Karyopharm Therapeutics

References

• Lilja JJ, Kivisto KT, Neuvonen PJ. Grapefruit juice increases serum concentrations of atorvastatin and has no effect on pravastatin. Clin Pharmacol Ther 1999;66:118-27.
• Lilja JJ, Kivisto KT, Neuvonen PJ. Grapefruit juice-simvastatin interaction: effect on serum concentrations of simvastatin, simvastatin acid, and HMG-CoA reductase inhibitors. Clin Pharmacol Ther 1998;64:477-83.
• Jetter A, Kinzig-Schippers M, Walchner-Bonjean M, et al. Effects of grapefruit juice on the pharmacokinetics of sildenafil. Clin Pharmacol Ther 2002;71:21-9.
• Fuhr U, Muller-Peltzer H, Kern R, et al. Effects of grapefruit juice and smoking on verapamil concentrations in steady state. Eur J Clin Pharmacol 2002;58:45-53.
• Kanazawa S, Ohkubo T, Sugawara K. The effects of grapefruit juice on the pharmacokinetics of erythromycin. Eur J Clin Pharmacol 2001;56:799-803.
• Charbit, B., Becquemont, L., Lepere, B., Peytavin, G., and Funck-Brentano, C. Pharmacokinetic and pharmacodynamic interaction between grapefruit juice and halofantrine. Clin Pharmacol Ther 2002;72(5):514-523.
• Tanaka S, Uchida S, Miyakawa S, Inui N, Takeuchi K, Watanabe H, Namiki N. Comparison of inhibitory duration of grapefruit juice on organic anion-transporting polypeptide and cytochrome P450 3A4. Biol Pharm Bull. 2013;36(12):1936-41.
• Bailey DG. Predicting clinical relevance of grapefruit-drug interactions: a complicated process. J Clin Pharm Ther. 2017 Apr;42(2):125-27.
• Mouly S, Lloret-Linares C, Sellire PO, Sene D, Bergmann JF. Is the clinical relevance of drug-food and drug-herb interactions limited to grapefruit juice and Saint-John's Wort? Pharmacol Res. 2017 Apr;118:82-92.
• Loretz C, Ho MD, Alam N, Mitchell W, Li AP. Application of cryopreserved human intestinal mucosa and cryopreserved human enterocytes in the evaluation of herb-drug interactions: evaluation of CYP3A inhibitory potential of grapefruit juice and commercial f
• Long Z, Ruan M, Wu W, Zeng Q, Li Q, Huang Z. The successful combination of grapefruit juice and venetoclax in an unfit acute myeloid leukemia patient with adverse risk: A case report. Front Oncol 2022;12:912696.

Selinexor Overview

• Selinexor is used along with dexamethasone to treat multiple myeloma (a type of cancer of the bone marrow) that has returned or that did not respond to at least 4 other treatments. Selinexor is also used with bortezomib and dexamethasone to treat multiple myeloma in patients who have previously been treated with at least one other medication. It is also used to treat certain types of diffuse large B-cell lymphoma (DLBCL; a type of cancer that begins in the white blood cells) in adults whose cancer has returned or is unresponsive to at least two other treatments. Selinexor is in a class of medications called selective inhibitors of nuclear export (SINE). It works by killing cancer cells.

Grapefruit - More Interactions

Grapefruit interacts with 963 drugs

Interaction Rating Key

These severity listings are for informational use only. Never start, stop or otherwise change your therapy before speaking with your provider.