Summary

Ketoconazole significantly increases dasatinib blood levels by inhibiting CYP3A4 metabolism, potentially leading to enhanced toxicity and adverse effects. This interaction requires careful monitoring and possible dose adjustments of dasatinib when used concurrently with ketoconazole.

Introduction

Dasatinib (Sprycel) is a second-generation tyrosine kinase inhibitor primarily used to treat chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). It works by blocking multiple tyrosine kinases including BCR-ABL, SRC family kinases, and others. 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 metabolizes many medications including dasatinib.

Mechanism of Interaction

The interaction between dasatinib and ketoconazole occurs through inhibition of the CYP3A4 enzyme system. Dasatinib is primarily metabolized by CYP3A4 in the liver, and ketoconazole is a potent CYP3A4 inhibitor. When ketoconazole blocks CYP3A4 activity, it significantly reduces dasatinib's metabolism and clearance from the body. This results in increased plasma concentrations of dasatinib, potentially reaching levels 5-fold higher than normal. The elevated dasatinib levels can persist for several days after ketoconazole discontinuation due to the irreversible nature of CYP3A4 inhibition by ketoconazole.

Risks and Symptoms

The primary clinical risks of this interaction include significantly increased dasatinib toxicity and adverse effects. Elevated dasatinib levels can lead to severe thrombocytopenia (low platelet count), neutropenia (low white blood cell count), and increased bleeding risk. Patients may experience enhanced cardiovascular toxicity, including QT prolongation, pulmonary arterial hypertension, and fluid retention. Gastrointestinal side effects such as nausea, vomiting, and diarrhea may also be intensified. The interaction is considered clinically significant and can potentially lead to life-threatening complications if not properly managed.

Management and Precautions

When concurrent use of dasatinib and ketoconazole cannot be avoided, dasatinib dose reduction is essential. Consider reducing dasatinib dose to 40mg once daily or 20mg twice daily, depending on the original dosing regimen. Close monitoring of complete blood counts, liver function tests, and cardiac function is required. Watch for signs of bleeding, bruising, or infection. If possible, consider alternative antifungal agents with less CYP3A4 inhibition such as fluconazole or caspofungin. If ketoconazole must be used, limit the duration of concurrent therapy and monitor dasatinib plasma levels if available. Patients should be counseled about increased bleeding risk and advised to report any unusual symptoms immediately.

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.