Summary

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

Introduction

Palbociclib (Ibrance) is a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor used primarily in the treatment of hormone receptor-positive, HER2-negative advanced or metastatic breast cancer. It works by blocking cell cycle progression and inhibiting tumor cell proliferation. Ketoconazole is a potent antifungal medication belonging to the azole class, commonly used to treat various fungal infections including candidiasis, dermatophytosis, and systemic mycoses. Ketoconazole is also known as a strong inhibitor of the cytochrome P450 3A4 (CYP3A4) enzyme system.

Mechanism of Interaction

The interaction between palbociclib and ketoconazole occurs through the inhibition of the CYP3A4 enzyme system. Palbociclib is primarily metabolized by CYP3A4, with this pathway accounting for the majority of its hepatic clearance. Ketoconazole is a potent competitive inhibitor of CYP3A4, significantly reducing the enzyme's activity. When administered concurrently, ketoconazole blocks the metabolism of palbociclib, leading to decreased clearance and increased systemic exposure. Clinical studies have shown that co-administration with strong CYP3A4 inhibitors like ketoconazole can increase palbociclib AUC (area under the curve) by approximately 87% and Cmax (maximum concentration) by about 34%.

Risks and Symptoms

The primary clinical risk of this interaction is significantly increased palbociclib exposure, which can lead to enhanced toxicity and adverse effects. Key risks include severe neutropenia, thrombocytopenia, and anemia, which are dose-dependent hematologic toxicities associated with palbociclib. Patients may experience increased fatigue, infections due to immunosuppression, bleeding complications, and gastrointestinal side effects such as nausea, diarrhea, and stomatitis. The interaction is classified as clinically significant, requiring careful monitoring and potential dose modifications. Severe hematologic toxicity may necessitate treatment delays, dose reductions, or discontinuation of therapy, potentially compromising cancer treatment efficacy.

Management and Precautions

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.