Summary

Voriconazole significantly increases sirolimus blood levels through CYP3A4 enzyme inhibition, potentially leading to sirolimus toxicity. This major drug interaction requires careful monitoring and dose adjustments when both medications are used concurrently.

Introduction

Voriconazole is a triazole antifungal medication commonly used to treat serious fungal infections, including invasive aspergillosis and candidemia. It works by inhibiting fungal cytochrome P450 enzymes essential for ergosterol synthesis. Sirolimus (rapamycin) is an immunosuppressive agent primarily used in organ transplant recipients to prevent rejection. It belongs to the mTOR inhibitor class and works by blocking T-cell activation and proliferation. Both medications are metabolized through the cytochrome P450 system, creating potential for significant drug interactions.

Mechanism of Interaction

The interaction between voriconazole and sirolimus occurs through competitive inhibition of the CYP3A4 enzyme system. Voriconazole is a potent inhibitor of CYP3A4, the primary enzyme responsible for sirolimus metabolism. When voriconazole blocks CYP3A4 activity, sirolimus clearance is significantly reduced, leading to elevated plasma concentrations. Studies have shown that voriconazole can increase sirolimus levels by 7-11 fold, with the effect persisting for several days after voriconazole discontinuation due to the long half-life of both medications.

Risks and Symptoms

The primary clinical risk of this interaction is sirolimus toxicity due to dramatically elevated drug levels. Symptoms of sirolimus toxicity include severe immunosuppression with increased infection risk, bone marrow suppression leading to thrombocytopenia and anemia, nephrotoxicity, hepatotoxicity, delayed wound healing, and increased risk of malignancy. The interaction is classified as major clinical significance, as it can result in serious adverse events requiring immediate medical intervention. Transplant patients are particularly vulnerable as they require therapeutic sirolimus levels to prevent organ rejection while avoiding toxic concentrations.

Management and Precautions

When concurrent use is necessary, sirolimus doses should be reduced by 80-90% and frequent therapeutic drug monitoring is essential. Sirolimus trough levels should be checked within 3-5 days of starting voriconazole and monitored closely throughout treatment. Consider alternative antifungal agents with less CYP3A4 inhibition potential, such as micafungin or caspofungin, when clinically appropriate. If voriconazole is discontinued, sirolimus levels may remain elevated for several days, requiring continued monitoring and gradual dose adjustments. Healthcare providers should maintain close communication between transplant and infectious disease teams to optimize both antifungal efficacy and immunosuppressive management.

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.

Sirolimus interactions with food and lifestyle

Sirolimus should be taken consistently either with or without food, as food can significantly affect absorption. High-fat meals can increase sirolimus blood levels by up to 35%, while taking it on an empty stomach may reduce absorption. Patients should avoid grapefruit and grapefruit juice, as they contain compounds that inhibit CYP3A4 enzymes and can significantly increase sirolimus blood levels, potentially leading to toxicity. St. John's wort should be avoided as it can decrease sirolimus levels by inducing CYP3A4 metabolism, potentially reducing the drug's effectiveness. Patients should limit sun exposure and use sunscreen, as sirolimus increases photosensitivity and skin cancer risk. Live vaccines should be avoided due to sirolimus's immunosuppressive effects.