Summary

Ketoconazole significantly increases pazopanib blood levels through CYP3A4 enzyme inhibition, leading to potentially dangerous toxicity. This combination is generally contraindicated and requires careful medical supervision if unavoidable.

Introduction

Pazopanib (Votrient) is an oral tyrosine kinase inhibitor primarily used to treat advanced renal cell carcinoma and soft tissue sarcoma. It works by blocking multiple receptor tyrosine kinases involved in tumor growth and angiogenesis. 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 CYP3A4 enzyme system, which metabolizes many medications including pazopanib.

Mechanism of Interaction

The interaction between pazopanib and ketoconazole occurs through inhibition of the cytochrome P450 3A4 (CYP3A4) enzyme system. Pazopanib is primarily metabolized by CYP3A4 enzymes in the liver. Ketoconazole is a potent CYP3A4 inhibitor that significantly reduces the metabolism of pazopanib, leading to increased plasma concentrations. Clinical studies have shown that ketoconazole can increase pazopanib exposure by approximately 66%, resulting in elevated drug levels that persist longer in the body.

Risks and Symptoms

The primary risk of combining pazopanib with ketoconazole is significantly increased pazopanib toxicity due to elevated drug concentrations. This can lead to severe adverse effects including hepatotoxicity (liver damage), QT interval prolongation with risk of cardiac arrhythmias, severe hypertension, and increased risk of bleeding. Other serious side effects may include severe diarrhea, fatigue, hand-foot syndrome, and potential for life-threatening complications. The increased exposure makes patients more susceptible to dose-limiting toxicities that may require treatment discontinuation.

Management and Precautions

The combination of pazopanib and ketoconazole should generally be avoided. If ketoconazole treatment is absolutely necessary, consider alternative antifungal agents with less CYP3A4 inhibition potential, such as fluconazole or newer azoles. If the combination cannot be avoided, pazopanib dose reduction may be required (typically to 400mg daily from the standard 800mg dose), with close monitoring for toxicity. Patients should be monitored with regular liver function tests, ECGs for QT prolongation, blood pressure monitoring, and complete blood counts. Healthcare providers should watch for signs of increased toxicity and be prepared to interrupt or discontinue pazopanib therapy if severe adverse effects occur.

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.