Summary

Enzalutamide and ketoconazole have a significant drug interaction where ketoconazole can substantially increase enzalutamide blood levels. This interaction occurs because ketoconazole is a strong CYP3A4 inhibitor that blocks the primary metabolic pathway of enzalutamide, potentially leading to increased toxicity and adverse effects.

Introduction

Enzalutamide (Xtandi) is an androgen receptor inhibitor primarily used to treat metastatic castration-resistant prostate cancer and metastatic castration-sensitive prostate cancer. It works by blocking androgen receptors and inhibiting androgen receptor nuclear translocation. Ketoconazole is an imidazole antifungal medication used to treat various fungal infections, including systemic mycoses, dermatophyte infections, and Candida infections. It works by inhibiting fungal cytochrome P450 enzymes, particularly 14α-demethylase, which is essential for ergosterol synthesis in fungal cell membranes.

Mechanism of Interaction

The interaction between enzalutamide and ketoconazole occurs through cytochrome P450 enzyme inhibition. Ketoconazole is a potent inhibitor of CYP3A4, the primary enzyme responsible for metabolizing enzalutamide. When ketoconazole inhibits CYP3A4, it significantly reduces the clearance of enzalutamide from the body, leading to increased plasma concentrations. Studies have shown that co-administration with strong CYP3A4 inhibitors like ketoconazole can increase enzalutamide exposure by approximately 2.2-fold, which may result in enhanced pharmacological effects and increased risk of adverse reactions.

Risks and Symptoms

The primary clinical risk of this interaction is increased enzalutamide toxicity due to elevated drug levels. Patients may experience enhanced adverse effects including increased risk of seizures (enzalutamide's most serious adverse effect), severe fatigue, dizziness, headache, hot flashes, hypertension, and potential cardiac effects. The increased exposure may also lead to more pronounced drug-related side effects such as cognitive impairment, falls, and fractures. Additionally, the interaction may affect the efficacy-to-toxicity ratio, potentially requiring dose modifications to maintain therapeutic benefit while minimizing harm.

Management and Precautions

Concurrent use of enzalutamide and ketoconazole should generally be avoided when possible. If co-administration is necessary, consider reducing the enzalutamide dose to 80 mg once daily and monitor patients closely for signs of increased toxicity, particularly neurological symptoms and seizure activity. Regular monitoring should include assessment of blood pressure, liver function tests, and evaluation for signs of drug-related adverse effects. Alternative antifungal agents with less CYP3A4 inhibition potential should be considered when treating fungal infections in patients taking enzalutamide. Healthcare providers should counsel patients about the increased risk of side effects and the importance of reporting any new or worsening symptoms promptly.

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.