Side Effects of Azoles in Treatment of AML

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In this segment, Kieren A. Marr, MD, professor of medicine in the Johns Hopkins School of Medicine, professor of oncology in the Sidney Kimmel Comprehensive Cancer Center, and medical director of the Transplant and Oncology Infectious Diseases program at Hopkins, discusses the varying side effects of azole drugs used for the treatment of patients with acute myeloid leukemia (AML).

Monitoring therapeutic drug levels with azole antifungal treatments can help to maximize efficacy while also avoiding side effects, especially for voriconazole, according to Kieren A. Marr, MD. Data suggest that a drug level higher than 5.5 in the blood progressively increases the risks for neurologic side effects, such as hallucinations, visual changes, and hepatotoxicities. Marr used a high-performance liquid chromatography assay to ensure that the drug levels for the early liquid formulations of posaconazole, which had unreliable absorption, were within the therapeutic range. Now that there are formulations with better absorption, questions remain as to whether this will lead to an increase in hepatotoxicities.

Despite being in the same class of drugs, each azole has a unique set of advantages and disadvantages, Marr notes. Compared with posaconazole, voriconazole has more variability in metabolism. Voriconazole may be easier to administer in the intravenous and oral formulation settings, says Marr. Voriconazole is associated with hepatotoxicities, neurologic toxicities, skin rash, and photosensitivities. Data also suggest that patients taking it for a prolonged time period in certain settings are at a higher risk for skin cancers. Posaconazole has broader efficacy against the organisms that cause mucormycosis. Although it is associated with hepatotoxicities, it tends to be better tolerated. It does not have the neurologic complications or rash, but there are some allergies associated with it.

If a patient has a lot of hepatotoxicities, Marr recommends against using voriconazole. Therefore, if a patient needs to take an oral drug for an extended period of time, such as in a prophylaxis setting, posaconazole is best. Posaconazole has been studied predominantly in a prevention setting, adds Marr, while voriconazole has been studied mostly in a therapeutic setting.