Summary

Everolimus and ketoconazole have a significant drug interaction due to ketoconazole'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. Ketoconazole is a potent antifungal medication belonging to the azole class, primarily used to treat serious systemic fungal infections. It is also sometimes used off-label for conditions like Cushing's syndrome due to its ability to inhibit steroid synthesis.

Mechanism of Interaction

The interaction between everolimus and ketoconazole occurs through the inhibition of the cytochrome P450 3A4 (CYP3A4) enzyme system. Everolimus is extensively metabolized by CYP3A4 in the liver and intestines, with this pathway accounting for the majority of its elimination from the body. Ketoconazole is a potent competitive inhibitor of CYP3A4, significantly reducing the enzyme's ability to metabolize everolimus. This inhibition leads to decreased clearance of everolimus, resulting in substantially increased plasma concentrations and prolonged half-life of the drug.

Risks and Symptoms

The primary risk of this interaction is everolimus toxicity due to elevated drug levels. Clinical manifestations may include severe immunosuppression leading to increased infection risk, delayed wound healing, mouth ulcers (stomatitis), pneumonitis, skin rash, fatigue, and gastrointestinal disturbances including nausea and diarrhea. In transplant patients, excessive immunosuppression may paradoxically increase the risk of organ rejection due to treatment interruptions. For cancer patients, dose-limiting toxicities may compromise treatment efficacy. Laboratory abnormalities such as elevated cholesterol, decreased blood counts, and liver enzyme elevations may also occur more frequently.

Management and Precautions

Concurrent use of everolimus and ketoconazole should generally be avoided when possible. If ketoconazole treatment is absolutely necessary, everolimus dosing requires significant reduction - typically to approximately 25% of the original dose, with close monitoring of everolimus blood levels and clinical response. Alternative antifungal agents with less CYP3A4 inhibition, such as fluconazole (at lower doses) or echinocandins, should be considered. If the combination cannot be avoided, frequent monitoring should include everolimus trough levels, complete blood counts, liver function tests, lipid profiles, and clinical assessment for signs of toxicity. Dose adjustments should be made based on therapeutic drug monitoring and clinical response.

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.

Ketoconazole interactions with food and lifestyle

Ketoconazole requires an acidic environment for optimal absorption. Take ketoconazole with food or an acidic beverage to enhance absorption. Avoid taking ketoconazole with antacids, H2 blockers, or proton pump inhibitors as these medications reduce stomach acid and significantly decrease ketoconazole absorption. If antacids must be used, take them at least 2 hours after ketoconazole. Alcohol should be avoided during ketoconazole treatment as both ketoconazole and alcohol can cause liver toxicity, and concurrent use may increase the risk of hepatotoxicity. Grapefruit juice may increase ketoconazole blood levels and should be avoided to prevent increased risk of side effects.