Summary

Everolimus and itraconazole have a significant drug interaction due to itraconazole's potent inhibition of CYP3A4, the primary enzyme responsible for everolimus metabolism. This interaction can lead to dramatically increased everolimus blood levels, potentially causing severe toxicity and requiring dose adjustments or alternative treatments.

Introduction

Everolimus is an mTOR (mechanistic target of rapamycin) inhibitor used as an immunosuppressant in organ transplant recipients and as an anticancer agent for various malignancies including renal cell carcinoma and neuroendocrine tumors. It belongs to the class of drugs known as sirolimus analogs. Itraconazole is a triazole antifungal medication used to treat various fungal infections, including aspergillosis, blastomycosis, and histoplasmosis. It works by inhibiting fungal cytochrome P450 enzymes, particularly 14α-demethylase, which is essential for ergosterol synthesis in fungal cell membranes.

Mechanism of Interaction

The interaction between everolimus and itraconazole occurs through cytochrome P450 enzyme inhibition. Itraconazole is a potent inhibitor of CYP3A4, the primary hepatic enzyme responsible for everolimus metabolism. When itraconazole inhibits CYP3A4, it significantly reduces the clearance of everolimus from the body, leading to increased plasma concentrations and prolonged half-life. This pharmacokinetic interaction can result in everolimus levels that are 3-5 times higher than normal, dramatically increasing the risk of dose-related adverse effects. The inhibition is competitive and reversible, but the effects can persist for several days after itraconazole discontinuation due to the drug's long half-life.

Risks and Symptoms

The primary risk of combining everolimus with itraconazole is everolimus toxicity due to elevated drug concentrations. Clinical risks include severe immunosuppression leading to increased susceptibility to infections and malignancies, particularly in transplant patients. Other significant adverse effects may include severe stomatitis, pneumonitis, delayed wound healing, hyperlipidemia, hyperglycemia, and renal dysfunction. In cancer patients, the risk of severe hematologic toxicity, including thrombocytopenia and anemia, is substantially increased. The interaction is considered clinically significant and may require treatment modification. Patients may experience life-threatening complications if the interaction is not properly managed, making this combination generally contraindicated or requiring extreme caution with intensive monitoring.

Management and Precautions

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.

Itraconazole interactions with food and lifestyle

Itraconazole should be taken with food to enhance absorption and bioavailability. The capsule formulation requires an acidic environment for optimal absorption, so it should be taken with a full meal or acidic beverage. Avoid taking itraconazole with antacids, H2 blockers, or proton pump inhibitors as these reduce stomach acid and significantly decrease drug absorption. Grapefruit juice should be avoided as it can increase itraconazole levels and risk of side effects. Alcohol should be used with caution as both itraconazole and alcohol can affect liver function.