Summary

Rapamycin (sirolimus) and voriconazole have a clinically significant drug interaction where voriconazole can substantially increase rapamycin blood levels. This interaction occurs through CYP3A4 enzyme inhibition and can lead to enhanced immunosuppression and increased risk of adverse effects.

Introduction

Rapamycin (sirolimus) is an immunosuppressive medication primarily used to prevent organ transplant rejection and treat certain autoimmune conditions. It belongs to the mTOR inhibitor class of drugs. Voriconazole is a triazole antifungal medication used to treat serious fungal infections, including invasive aspergillosis and candidemia. Both medications are commonly prescribed in transplant patients, making their interaction clinically relevant.

Mechanism of Interaction

The interaction between rapamycin and voriconazole occurs through inhibition of the cytochrome P450 3A4 (CYP3A4) enzyme system. Voriconazole is a potent CYP3A4 inhibitor, while rapamycin is extensively metabolized by this same enzyme pathway. When voriconazole inhibits CYP3A4, it significantly reduces rapamycin metabolism, leading to increased rapamycin plasma concentrations and prolonged elimination half-life. This can result in rapamycin levels that are 2-11 times higher than expected.

Risks and Symptoms

The primary clinical risk of this interaction is excessive immunosuppression due to elevated rapamycin levels. This can increase susceptibility to infections, including opportunistic pathogens, and may elevate the risk of certain malignancies. Additional risks include enhanced rapamycin-related adverse effects such as hyperlipidemia, thrombocytopenia, anemia, delayed wound healing, and nephrotoxicity. In transplant patients, while over-immunosuppression is the main concern, the interaction paradoxically helps maintain therapeutic rapamycin levels when both drugs are needed.

Management and Precautions

When concurrent use is necessary, rapamycin doses should be significantly reduced (often by 50-90%) and therapeutic drug monitoring should be intensified. Rapamycin trough levels should be checked more frequently, typically within 3-5 days of starting voriconazole and regularly thereafter. Consider alternative antifungal agents with less CYP3A4 inhibition if clinically appropriate. Monitor patients closely for signs of over-immunosuppression, infections, and rapamycin-related adverse effects. Dose adjustments should be made based on therapeutic drug monitoring results and clinical response. Consultation with clinical pharmacists or transplant specialists is recommended for optimal management.

Rapamycin interactions with food and lifestyle

Rapamycin should be taken consistently either with or without food, as food can significantly affect absorption. High-fat meals can increase rapamycin blood levels by up to 35%, while the timing and fat content of meals can cause variable drug absorption. Grapefruit juice should be avoided as it can increase rapamycin blood levels and potentially lead to increased side effects. Patients should maintain consistent dietary habits and timing of meals when taking rapamycin to ensure stable drug levels.

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.