Summary

Everolimus and voriconazole have a clinically significant drug interaction where voriconazole significantly increases everolimus blood levels by inhibiting CYP3A4 metabolism. This interaction can lead to increased everolimus toxicity and requires careful monitoring and dose adjustments.

Introduction

Everolimus is an mTOR (mechanistic target of rapamycin) inhibitor used as an immunosuppressant in organ transplant recipients and as an anticancer agent in various malignancies. It belongs to the class of drugs known as sirolimus analogs and requires careful therapeutic drug monitoring due to its narrow therapeutic window. Voriconazole is a triazole antifungal medication used to treat serious fungal infections, including invasive aspergillosis and candidemia. It is a potent inhibitor of several cytochrome P450 enzymes, particularly CYP3A4, which makes it prone to numerous drug interactions.

Mechanism of Interaction

The interaction between everolimus and voriconazole occurs through competitive inhibition of the CYP3A4 enzyme system. Everolimus is extensively metabolized by CYP3A4 in the liver and intestines, with this pathway being responsible for the majority of its clearance from the body. Voriconazole is a potent CYP3A4 inhibitor that significantly reduces the metabolic clearance of everolimus, leading to substantially increased plasma concentrations. Studies have shown that voriconazole can increase everolimus exposure (AUC) by up to 3-4 fold, with peak concentrations also significantly elevated. This inhibition is dose-dependent and reversible upon discontinuation of voriconazole.

Risks and Symptoms

The primary clinical risk of this interaction is everolimus toxicity due to elevated drug concentrations. Common manifestations of everolimus toxicity include severe immunosuppression leading to increased infection risk, delayed wound healing, mouth ulcers (aphthous stomatitis), pneumonitis, hyperlipidemia, proteinuria, and thrombocytopenia. In transplant patients, excessive immunosuppression may paradoxically increase the risk of opportunistic infections while potentially causing over-immunosuppression. In oncology patients, dose-limiting toxicities may include severe mucositis, pneumonitis, and metabolic complications. The interaction is considered clinically significant and requires proactive management to prevent serious adverse events.

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.

Voriconazole interactions with food and lifestyle

Voriconazole should be taken on an empty stomach, at least 1 hour before or 2 hours after meals, as food significantly reduces absorption and bioavailability. High-fat meals can decrease voriconazole absorption by up to 22%. Patients should avoid grapefruit and grapefruit juice during treatment, as these can increase voriconazole blood levels and risk of toxicity. Alcohol consumption should be avoided or limited, as both voriconazole and alcohol are metabolized by the liver and concurrent use may increase the risk of liver toxicity. Patients should also avoid prolonged sun exposure and use adequate sun protection, as voriconazole can cause photosensitivity reactions and increase risk of skin cancer with long-term use.