Summary

Cyclosporine significantly increases etoposide plasma concentrations by inhibiting P-glycoprotein-mediated efflux, leading to enhanced toxicity. This interaction requires careful monitoring and potential dose adjustments when these medications are used concurrently.

Introduction

Etoposide is a topoisomerase II inhibitor chemotherapy agent commonly used to treat various cancers including lung cancer, testicular cancer, and lymphomas. It works by preventing DNA repair and causing cancer cell death. Cyclosporine is a calcineurin inhibitor immunosuppressant primarily used to prevent organ transplant rejection and treat certain autoimmune conditions. Both medications are substrates of P-glycoprotein, a drug efflux pump that affects their distribution and elimination.

Mechanism of Interaction

The interaction between etoposide and cyclosporine occurs through P-glycoprotein inhibition. Cyclosporine is a potent inhibitor of P-glycoprotein, a membrane transporter responsible for effluxing etoposide from cells. When cyclosporine inhibits P-glycoprotein, it reduces etoposide clearance and increases its intracellular accumulation. This results in significantly elevated etoposide plasma concentrations (up to 80% increase in AUC) and prolonged elimination half-life, leading to enhanced pharmacological effects and increased risk of toxicity.

Risks and Symptoms

The primary clinical risk of this interaction is increased etoposide toxicity, particularly severe myelosuppression (bone marrow suppression) leading to neutropenia, thrombocytopenia, and anemia. Patients may experience increased gastrointestinal toxicity including severe nausea, vomiting, and mucositis. There is also an elevated risk of secondary malignancies with prolonged exposure to higher etoposide concentrations. The interaction is considered clinically significant and can lead to life-threatening complications if not properly managed.

Management and Precautions

When concurrent use is necessary, consider reducing etoposide dose by 25-50% and implement intensive monitoring. Monitor complete blood counts weekly during treatment and for several weeks after completion. Watch for signs of infection, bleeding, or unusual bruising. Consider therapeutic drug monitoring of etoposide levels if available. Evaluate the necessity of cyclosporine and consider alternative immunosuppressants if clinically appropriate. Provide supportive care including growth factor support for severe neutropenia. Educate patients about infection precautions and when to seek immediate medical attention.

Cyclosporine interactions with food and lifestyle

Cyclosporine has several important food and lifestyle interactions that patients should be aware of: **Grapefruit and Grapefruit Juice:** Avoid grapefruit and grapefruit juice while taking cyclosporine. Grapefruit contains compounds that inhibit CYP3A4 enzymes, which can significantly increase cyclosporine blood levels and potentially lead to toxicity. This interaction is well-documented and patients are specifically warned to avoid grapefruit products. **High-Fat Meals:** Taking cyclosporine with high-fat meals can increase the absorption of the medication, potentially leading to higher blood levels. While this doesn't require complete avoidance, patients should maintain consistent dietary habits and take cyclosporine at the same time each day relative to meals. **St. John's Wort:** This herbal supplement should be avoided as it can significantly decrease cyclosporine blood levels by inducing CYP3A4 enzymes, potentially leading to organ rejection in transplant patients or treatment failure. **Alcohol:** While moderate alcohol consumption may not be completely contraindicated, patients should discuss alcohol use with their healthcare provider as cyclosporine can affect liver function, and alcohol may compound these effects. **Sun Exposure:** Patients taking cyclosporine have an increased risk of skin cancer and should limit sun exposure, use sunscreen with high SPF, and wear protective clothing when outdoors.