Summary

Ketoconazole significantly increases bortezomib plasma concentrations by inhibiting CYP3A4 metabolism, potentially leading to enhanced toxicity. This interaction requires careful monitoring and possible dose adjustments when concurrent use is necessary.

Introduction

Bortezomib (Velcade) is a proteasome inhibitor primarily used to treat multiple myeloma and mantle cell lymphoma. It works by blocking the proteasome complex, leading to cancer cell death. Ketoconazole is a potent antifungal medication belonging to the azole class, commonly used to treat serious fungal infections. It is also a strong inhibitor of the cytochrome P450 3A4 (CYP3A4) enzyme system, which metabolizes many medications including bortezomib.

Mechanism of Interaction

The interaction between bortezomib and ketoconazole occurs through CYP3A4 enzyme inhibition. Bortezomib is primarily metabolized by CYP3A4, CYP2C19, and CYP1A2 enzymes. Ketoconazole is a potent CYP3A4 inhibitor that significantly reduces bortezomib clearance, leading to increased plasma concentrations and prolonged half-life. Studies have shown that ketoconazole can increase bortezomib AUC (area under the curve) by approximately 35%, indicating substantially higher drug exposure when used concurrently.

Risks and Symptoms

The primary clinical risk of this interaction is increased bortezomib toxicity due to elevated plasma concentrations. Patients may experience enhanced side effects including severe peripheral neuropathy, thrombocytopenia, neutropenia, gastrointestinal toxicity (nausea, vomiting, diarrhea), and fatigue. The risk of dose-limiting toxicities is significantly increased, potentially requiring treatment delays or discontinuation. Patients with pre-existing neuropathy or hematologic abnormalities are at particularly high risk for severe complications.

Management and Precautions

When concurrent use is necessary, consider reducing the bortezomib dose and implement enhanced monitoring protocols. Monitor complete blood counts more frequently for signs of myelosuppression, assess neurological function regularly for peripheral neuropathy, and watch for gastrointestinal toxicity. Consider alternative antifungal agents with less CYP3A4 inhibition potential, such as fluconazole or micafungin, when clinically appropriate. If ketoconazole must be used, start with reduced bortezomib doses and titrate based on tolerance. Maintain close communication between oncology and infectious disease teams to optimize both cancer treatment and antifungal therapy.

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.