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 adverse effects.

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 cytochrome P450 enzyme system, specifically CYP3A4. 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, effectively blocking the enzyme's ability to metabolize everolimus. When ketoconazole inhibits CYP3A4, everolimus clearance is significantly reduced, leading to increased plasma concentrations and prolonged half-life. Studies have shown that ketoconazole can increase everolimus exposure (AUC) by up to 15-fold and peak concentrations by 4-fold.

Risks and Symptoms

The primary risk of this interaction is everolimus toxicity due to dramatically elevated drug levels. Clinical manifestations may include severe immunosuppression leading to increased infection risk, delayed wound healing, and opportunistic infections. Other serious adverse effects include severe mucositis, pneumonitis, renal dysfunction, metabolic complications such as hyperglycemia and hyperlipidemia, hematologic toxicity including thrombocytopenia and anemia, and hepatotoxicity. In transplant patients, paradoxically, excessive everolimus levels may also increase the risk of acute rejection due to dose-related toxicity requiring drug discontinuation. The interaction is considered clinically significant and potentially life-threatening, requiring careful management or avoidance of the combination.

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.

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.