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 primarily used to prevent organ transplant rejection and treat certain autoimmune conditions. It belongs to the mTOR inhibitor class of drugs. Ketoconazole is a potent antifungal medication from the azole class, used to treat serious fungal infections. It is also known as a strong inhibitor of the CYP3A4 enzyme system, which metabolizes many medications including sirolimus.

Mechanism of Interaction

The interaction between sirolimus and ketoconazole occurs through inhibition of the cytochrome P450 3A4 (CYP3A4) enzyme system. Sirolimus is extensively metabolized by CYP3A4 enzymes in the liver and intestines. Ketoconazole is a potent CYP3A4 inhibitor that significantly reduces the metabolism of sirolimus, leading to increased bioavailability and elevated plasma concentrations. This can result in sirolimus levels that are 3-5 times higher than normal, dramatically increasing the drug's pharmacological effects.

Risks and Symptoms

The primary risks of this interaction include significantly elevated sirolimus blood levels leading to enhanced immunosuppression, increased susceptibility to infections, delayed wound healing, and higher risk of malignancies. Patients may experience dose-related adverse effects such as hyperlipidemia, hypertension, kidney dysfunction, mouth ulcers, and bone marrow suppression. The interaction can also increase the risk of sirolimus-related pulmonary toxicity and impaired glucose tolerance. Overdose symptoms may occur even with standard sirolimus dosing when combined with ketoconazole.

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 ketoconazole and monitored closely throughout treatment. Consider alternative antifungal agents with less CYP3A4 inhibition potential, such as fluconazole (though it also requires monitoring) or echinocandins. If ketoconazole must be used, ensure close collaboration between prescribing physicians, frequent laboratory monitoring including complete blood counts, liver function tests, and lipid panels. Patients should be educated about signs of immunosuppression and advised to report any unusual symptoms immediately.

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.