Summary

Arsenic trioxide and ketoconazole have a significant drug interaction that increases the risk of QT interval prolongation and potentially life-threatening cardiac arrhythmias. Both medications can independently prolong the QT interval, and their concurrent use creates an additive effect that substantially elevates the risk of torsades de pointes.

Introduction

Arsenic trioxide is an antineoplastic agent primarily used in the treatment of acute promyelocytic leukemia (APL), particularly in relapsed or refractory cases. It belongs to the class of heavy metal compounds and works by inducing apoptosis in leukemic cells. Ketoconazole is a broad-spectrum antifungal medication belonging to the azole class of antifungals. It is used to treat various fungal infections and works by inhibiting fungal cytochrome P450 enzymes, particularly CYP51, which is essential for ergosterol synthesis in fungal cell membranes.

Mechanism of Interaction

The interaction between arsenic trioxide and ketoconazole occurs through their combined effects on cardiac electrophysiology. Arsenic trioxide directly affects cardiac ion channels, particularly potassium channels (hERG/IKr), leading to delayed ventricular repolarization and QT interval prolongation. Ketoconazole also blocks hERG potassium channels and can prolong the QT interval through similar mechanisms. When used concurrently, these medications create an additive effect on QT prolongation, significantly increasing the risk of developing torsades de pointes, a potentially fatal ventricular arrhythmia. Additionally, ketoconazole may inhibit the metabolism of arsenic trioxide through CYP enzyme interactions, potentially increasing arsenic trioxide plasma concentrations.

Risks and Symptoms

The primary clinical risk of combining arsenic trioxide and ketoconazole is the development of serious cardiac arrhythmias, particularly torsades de pointes, which can be life-threatening. Patients may experience symptoms such as dizziness, syncope, palpitations, or sudden cardiac death. The risk is particularly elevated in patients with pre-existing cardiac conditions, electrolyte imbalances (hypokalemia, hypomagnesemia), or other risk factors for QT prolongation. Additional risks include increased arsenic trioxide toxicity due to potential metabolic interactions, leading to enhanced side effects such as peripheral neuropathy, hepatotoxicity, and bone marrow suppression. The combination may also increase the risk of other cardiovascular complications including heart block and ventricular fibrillation.

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.