Summary

Diltiazem significantly increases sunitinib plasma concentrations through CYP3A4 enzyme inhibition, potentially leading to enhanced toxicity. This interaction requires careful monitoring and possible dose adjustments when these medications are used concurrently.

Introduction

Sunitinib (Sutent) is a multi-targeted tyrosine kinase inhibitor primarily used to treat renal cell carcinoma, gastrointestinal stromal tumors (GIST), and pancreatic neuroendocrine tumors. It works by blocking multiple receptor tyrosine kinases involved in tumor growth and angiogenesis. Diltiazem is a non-dihydropyridine calcium channel blocker commonly prescribed for hypertension, angina, and certain arrhythmias. It works by blocking calcium channels in the heart and blood vessels, reducing cardiac contractility and causing vasodilation.

Mechanism of Interaction

The interaction between sunitinib and diltiazem occurs through inhibition of the cytochrome P450 3A4 (CYP3A4) enzyme system. Sunitinib is primarily metabolized by CYP3A4 to its active metabolite SU12662. Diltiazem is a moderate CYP3A4 inhibitor that can significantly reduce the metabolism of sunitinib, leading to increased plasma concentrations of both sunitinib and its active metabolite. This pharmacokinetic interaction can result in a 51% increase in sunitinib exposure when co-administered with strong CYP3A4 inhibitors, with moderate inhibitors like diltiazem causing proportionally significant increases.

Risks and Symptoms

The primary clinical risk of this interaction is increased sunitinib toxicity due to elevated drug concentrations. Common sunitinib adverse effects that may be intensified include severe diarrhea, fatigue, hand-foot syndrome, hypertension, neutropenia, thrombocytopenia, and hepatotoxicity. Cardiovascular risks are particularly concerning as both drugs can affect cardiac function - sunitinib may cause QT prolongation and decreased left ventricular ejection fraction, while diltiazem affects cardiac conduction. The combination may increase the risk of serious cardiac adverse events, bleeding complications due to thrombocytopenia, and severe gastrointestinal toxicity.

Management and Precautions

When concurrent use is necessary, consider reducing the sunitinib dose by approximately 12.5-25mg daily and monitor closely for increased toxicity. Regular monitoring should include complete blood counts, liver function tests, thyroid function, blood pressure, and cardiac function assessment including ECG and echocardiogram. Patients should be educated about signs of increased toxicity and advised to report symptoms promptly. Alternative antihypertensive agents that do not significantly inhibit CYP3A4, such as ACE inhibitors or ARBs, should be considered when possible. If diltiazem must be continued, more frequent clinical assessments and laboratory monitoring are essential, with dose modifications based on tolerability and toxicity profiles.

Sunitinib interactions with food and lifestyle

Sunitinib should be taken with or without food as food does not significantly affect absorption. However, patients should avoid grapefruit and grapefruit juice while taking sunitinib, as grapefruit can increase sunitinib blood levels and potentially increase the risk of side effects. St. John's wort should also be avoided as it may decrease sunitinib effectiveness by reducing drug levels in the blood. Patients should limit alcohol consumption as both sunitinib and alcohol can cause liver toxicity, and combining them may increase this risk.

Diltiazem interactions with food and lifestyle

Grapefruit and grapefruit juice should be avoided while taking diltiazem as they can significantly increase blood levels of the medication, potentially leading to dangerous drops in blood pressure and heart rate. Alcohol consumption should be limited or avoided as it can enhance the blood pressure-lowering effects of diltiazem and increase the risk of dizziness, fainting, and falls. Patients should also be cautious when standing up quickly or engaging in activities requiring alertness, as diltiazem can cause dizziness and lightheadedness, especially when starting treatment or increasing the dose.