Summary

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

Introduction

Itraconazole is a triazole antifungal medication commonly used to treat various fungal infections, including aspergillosis, candidiasis, and dermatophyte infections. It works by inhibiting fungal cytochrome P450 enzymes, particularly 14α-demethylase. Sirolimus (rapamycin) is an immunosuppressive agent primarily used in organ transplant recipients to prevent rejection and in certain autoimmune conditions. It belongs to the mTOR (mechanistic target of rapamycin) inhibitor class and works by blocking T-cell activation and proliferation.

Mechanism of Interaction

The interaction between itraconazole and sirolimus occurs through competitive inhibition of the cytochrome P450 3A4 (CYP3A4) enzyme system. Itraconazole is a potent CYP3A4 inhibitor, while sirolimus is extensively metabolized by this same enzyme pathway. When itraconazole inhibits CYP3A4, it significantly reduces the metabolism and clearance of sirolimus, leading to substantially elevated sirolimus plasma concentrations. This pharmacokinetic interaction can result in sirolimus levels that are 3-11 times higher than normal, depending on the dose and duration of itraconazole therapy.

Risks and Symptoms

The primary clinical risk of this interaction is sirolimus toxicity due to elevated drug levels. Potential adverse effects include severe immunosuppression leading to increased infection risk, bone marrow suppression, nephrotoxicity, hepatotoxicity, hyperlipidemia, delayed wound healing, and increased risk of malignancy. Patients may experience symptoms such as fatigue, mouth ulcers, diarrhea, elevated liver enzymes, decreased white blood cell counts, and impaired kidney function. In transplant patients, while the risk of rejection may decrease due to higher immunosuppression, the overall clinical outcome may be compromised due to toxicity-related complications.

Management and Precautions

When concurrent use is necessary, sirolimus doses should be significantly reduced (often by 75-90%) and frequent therapeutic drug monitoring is essential. Sirolimus trough levels should be checked within 3-5 days of starting itraconazole and monitored closely throughout treatment. Consider alternative antifungal agents with less CYP3A4 inhibition potential, such as fluconazole (though it also has some interaction) or echinocandins like caspofungin. If itraconazole must be used, consider temporary discontinuation of sirolimus in consultation with the transplant team, depending on the clinical scenario. Monitor for signs of sirolimus toxicity including complete blood count, liver function tests, kidney function, and lipid levels. Upon discontinuation of itraconazole, sirolimus levels may take several days to weeks to normalize, requiring gradual dose adjustments back to baseline.

Itraconazole interactions with food and lifestyle

Itraconazole should be taken with food to enhance absorption and bioavailability. The capsule formulation requires an acidic environment for optimal absorption, so it should be taken with a full meal or acidic beverage. Avoid taking itraconazole with antacids, H2 blockers, or proton pump inhibitors as these reduce stomach acid and significantly decrease drug absorption. Grapefruit juice should be avoided as it can increase itraconazole levels and risk of side effects. Alcohol should be used with caution as both itraconazole and alcohol can affect liver function.

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.