Summary

Ketoconazole significantly increases sirolimus blood levels through CYP3A4 enzyme inhibition, potentially leading to enhanced immunosuppression and increased risk of adverse effects. This interaction requires careful monitoring and possible dose adjustments when these medications are used together.

Introduction

Sirolimus (brand name Rapamune) is an immunosuppressive medication belonging to the mTOR inhibitor class, primarily used to prevent organ transplant rejection and treat certain autoimmune conditions. Ketoconazole is a potent antifungal medication from the azole class, used to treat serious fungal infections. Both medications are metabolized through similar pathways in the liver, which can lead to clinically significant drug interactions when used concurrently.

Mechanism of Interaction

The interaction between sirolimus and ketoconazole occurs through inhibition of the cytochrome P450 3A4 (CYP3A4) enzyme system. Ketoconazole is a potent CYP3A4 inhibitor that significantly reduces the metabolism of sirolimus, which is primarily metabolized by this same enzyme pathway. This inhibition leads to decreased clearance of sirolimus from the body, resulting in substantially elevated sirolimus blood concentrations that can persist for several days after ketoconazole administration.

Risks and Symptoms

The primary risk of this interaction is sirolimus toxicity due to elevated drug levels, which can manifest as severe immunosuppression, increased susceptibility to infections, delayed wound healing, and potential organ toxicity. Patients may experience symptoms such as mouth ulcers, diarrhea, hypertriglyceridemia, thrombocytopenia, and increased risk of malignancy. The interaction can increase sirolimus levels by 10-fold or more, making this a high-severity drug interaction that requires immediate attention and management.

Management and Precautions

When concurrent use is necessary, sirolimus doses should be significantly reduced (often by 80-90%) and frequent therapeutic drug monitoring is essential. Sirolimus blood levels should be checked within 3-5 days of starting ketoconazole and regularly thereafter. Alternative antifungal agents with less CYP3A4 inhibition potential should be considered when possible. If ketoconazole is discontinued, sirolimus doses may need gradual upward adjustment with continued monitoring. Patients should be closely observed for signs of immunosuppression, infection, and other sirolimus-related adverse effects throughout treatment.

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.

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.