Summary

Everolimus and cyclosporine have a significant pharmacokinetic interaction where cyclosporine increases everolimus blood levels by inhibiting CYP3A4 and P-glycoprotein. This interaction requires careful dose adjustments and therapeutic drug monitoring to prevent toxicity while maintaining immunosuppressive efficacy.

Introduction

Everolimus is an mTOR (mechanistic target of rapamycin) inhibitor used as an immunosuppressant in organ transplantation and as an anticancer agent in certain malignancies. It belongs to the sirolimus family of drugs and works by blocking cell proliferation and angiogenesis. Cyclosporine is a calcineurin inhibitor immunosuppressant widely used in organ transplantation to prevent rejection. It suppresses T-cell activation and is considered a cornerstone of immunosuppressive therapy. Both medications are commonly used together in transplant protocols, making their interaction clinically relevant.

Mechanism of Interaction

The interaction between everolimus and cyclosporine occurs through multiple pathways. Cyclosporine is a potent inhibitor of CYP3A4, the primary enzyme responsible for everolimus metabolism. Additionally, cyclosporine inhibits P-glycoprotein, an efflux transporter that affects everolimus absorption and distribution. When co-administered, cyclosporine significantly increases everolimus plasma concentrations by reducing its hepatic metabolism and intestinal efflux. Studies show that cyclosporine can increase everolimus exposure (AUC) by 2-5 fold, with the magnitude of interaction varying based on cyclosporine formulation and dosing.

Risks and Symptoms

The primary risk of this interaction is everolimus toxicity due to elevated blood levels. Increased everolimus concentrations can lead to enhanced immunosuppression, increasing the risk of infections and malignancies. Other significant adverse effects include hyperlipidemia, proteinuria, delayed wound healing, mouth ulcers, and pneumonitis. Conversely, if the interaction is not properly managed, subtherapeutic everolimus levels may result in inadequate immunosuppression and increased risk of organ rejection. The narrow therapeutic window of both drugs makes this interaction particularly challenging to manage clinically.

Management and Precautions

Management of the everolimus-cyclosporine interaction requires several key strategies. First, everolimus doses should be reduced by approximately 50% when initiating cyclosporine co-therapy. Therapeutic drug monitoring is essential, with everolimus trough levels typically targeted between 3-8 ng/mL in transplant patients. Regular monitoring should include complete blood counts, liver function tests, lipid profiles, and renal function. Consider using reduced-dose cyclosporine protocols when possible to minimize the interaction. Patients should be counseled about signs of infection, delayed wound healing, and other toxicity symptoms. Close collaboration between transplant teams and clinical pharmacists is recommended for optimal dose optimization and monitoring.

Everolimus interactions with food and lifestyle

Everolimus should be taken consistently either with food or without food, but not alternating between the two, as food can significantly affect absorption and blood levels. Grapefruit and grapefruit juice should be avoided as they can increase everolimus blood levels and potentially lead to increased side effects. St. John's wort should be avoided as it can decrease everolimus effectiveness by reducing blood levels. Live vaccines should be avoided during everolimus treatment due to immunosuppressive effects.

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.