Summary

Ibrutinib and ketoconazole have a significant drug interaction due to ketoconazole's strong inhibition of CYP3A4, the primary enzyme responsible for ibrutinib metabolism. This interaction can lead to substantially increased ibrutinib plasma concentrations, potentially resulting in enhanced toxicity and adverse effects.

Introduction

Ibrutinib is an oral Bruton's tyrosine kinase (BTK) inhibitor used to treat various B-cell malignancies, including chronic lymphocytic leukemia (CLL), mantle cell lymphoma, and Waldenström's macroglobulinemia. Ketoconazole is a potent antifungal medication belonging to the azole class, commonly used to treat serious fungal infections. It is also known as a strong inhibitor of the cytochrome P450 3A4 (CYP3A4) enzyme system, which plays a crucial role in drug metabolism.

Mechanism of Interaction

The interaction between ibrutinib and ketoconazole occurs through competitive inhibition of the CYP3A4 enzyme system. Ibrutinib is primarily metabolized by CYP3A4, and ketoconazole is a potent CYP3A4 inhibitor. When administered concurrently, ketoconazole significantly reduces ibrutinib's hepatic metabolism, leading to increased plasma concentrations and prolonged elimination half-life. Clinical studies have shown that ketoconazole can increase ibrutinib exposure by approximately 29-fold, representing one of the most significant pharmacokinetic interactions reported with ibrutinib.

Risks and Symptoms

The primary risk of this interaction is ibrutinib toxicity due to dramatically elevated plasma concentrations. Patients may experience increased incidence and severity of adverse effects including bleeding complications, atrial fibrillation, hypertension, diarrhea, fatigue, and cytopenias. The bleeding risk is particularly concerning as ibrutinib affects platelet function, and increased concentrations may lead to life-threatening hemorrhagic events. Additionally, patients may experience tumor lysis syndrome or severe infections due to enhanced immunosuppressive effects at higher ibrutinib concentrations.

Management and Precautions

Concurrent use of ibrutinib and ketoconazole should be avoided whenever possible. If ketoconazole treatment is absolutely necessary, ibrutinib should be temporarily discontinued during ketoconazole therapy and for several days after ketoconazole discontinuation to allow for enzyme recovery. Alternative antifungal agents with minimal CYP3A4 inhibition, such as fluconazole (at low doses) or echinocandins, should be considered. If no alternatives exist, extreme caution is required with frequent monitoring for ibrutinib toxicity, including complete blood counts, bleeding assessments, cardiac monitoring, and close clinical observation. Healthcare providers should also review all concomitant medications for other CYP3A4 inhibitors that could compound this interaction.

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.