Summary

Rifampin significantly reduces everolimus blood levels through CYP3A4 enzyme induction, potentially leading to treatment failure. This major drug interaction requires careful monitoring and possible dose adjustments when both medications are used concurrently.

Introduction

Everolimus is an mTOR (mechanistic target of rapamycin) inhibitor used as an immunosuppressant in organ transplant recipients and as an anticancer agent for various malignancies including renal cell carcinoma and neuroendocrine tumors. Rifampin is a potent antibiotic belonging to the rifamycin class, primarily used to treat tuberculosis and other mycobacterial infections. It is also used for certain atypical mycobacterial infections and as prophylaxis in close contacts of meningococcal disease.

Mechanism of Interaction

The interaction between everolimus and rifampin occurs through rifampin's potent induction of the CYP3A4 enzyme system. Everolimus is extensively metabolized by CYP3A4 in the liver and intestines. When rifampin is co-administered, it significantly increases CYP3A4 enzyme activity, leading to enhanced metabolism and clearance of everolimus. This results in substantially reduced everolimus plasma concentrations, potentially falling below therapeutic levels. Rifampin also induces P-glycoprotein, which may further reduce everolimus bioavailability.

Risks and Symptoms

The primary clinical risk of this interaction is therapeutic failure due to subtherapeutic everolimus levels. In transplant patients, this could lead to organ rejection, while in cancer patients, it may result in disease progression or treatment failure. Studies have shown that rifampin can reduce everolimus exposure by up to 63-85%. The interaction begins within days of rifampin initiation and persists for several weeks after rifampin discontinuation due to the time required for enzyme levels to normalize. This interaction is classified as clinically significant and requires proactive management.

Management and Precautions

When concurrent use is necessary, everolimus doses may need to be increased significantly (potentially 2-5 fold) with close therapeutic drug monitoring. Everolimus blood levels should be checked frequently, typically within 1-2 weeks of rifampin initiation or dose changes. Alternative antibiotics should be considered when possible, such as other anti-tuberculosis agents that don't induce CYP3A4. If rifampin must be used, consider temporary everolimus dose increases with careful monitoring of both efficacy and toxicity. After rifampin discontinuation, everolimus doses should be reduced gradually with continued monitoring as enzyme activity normalizes over 2-4 weeks. Consultation with clinical pharmacists and specialists is recommended for optimal management.

Everolimus interactions with food and lifestyle

Everolimus should be taken consistently either with food or without food, but not alternating between the two, as food can significantly affect absorption and blood levels. Grapefruit and grapefruit juice should be avoided as they can increase everolimus blood levels and potentially lead to increased side effects. St. John's wort should be avoided as it can decrease everolimus effectiveness by reducing blood levels. Live vaccines should be avoided during everolimus treatment due to immunosuppressive effects.

Rifampin interactions with food and lifestyle

Rifampin should be taken on an empty stomach, at least 1 hour before or 2 hours after meals, as food can significantly reduce its absorption and effectiveness. Alcohol consumption should be avoided or limited while taking rifampin, as both rifampin and alcohol can cause liver toxicity, and the combination may increase the risk of hepatotoxicity. Patients should be counseled to take rifampin consistently either with or without food (preferably without) to maintain consistent blood levels.