Drug-Drug Interactions of Triazole Antifungal Agents in Multimorbid Patients and Implications for Patient Care

Abstract

Drug interactions occur frequently with triazole antifungal agents because of their properties as inhibitors of 1 or more phase 1 (cytochrome P450) biotransformation enzymes and, possibly, as inhibitors or substrates of a phase 2 biotransformation enzyme or transporter protein. Multimorbid patients, including those with hematologic malignancies or other cancers, hematopoietic stem cell or organ transplant recipients, patients infected with the human immunodeficiency virus, and those in the intensive care unit, are at increased risk for drug interactions because they typically require several concomitant medications. They may also be extremely vulnerable to the clinical signs and symptoms of drug interactions. This review describes clinically significant drug interactions most frequently seen in multimorbid patients who receive systemic therapy with triazole antifungals for the prophylaxis or treatment of invasive fungal infections; including interactions with corticosteroids, immunosuppressants, anti-infective drugs, benzodiazepines, opioid analgesics, statins, anticoagulants, anticonvulsants, and drugs affecting gastric pH. The review also describes recommendations concerning contraindications and dose-modification strategies. The azoles differ markedly in their pharmacokinetic and antifungal properties, safety and tolerability, and drug-interaction profiles. Many drug interactions can be prevented if clinicians are thoroughly familiar with the pharmacokinetic profiles of different azoles, follow contraindications and dose-modification recommendations, and switch azoles when possible to achieve the best combination of clinical efficacy and safety. Therapeutic drug monitoring can help optimize treatment and prevent underdosing or overdosing of drugs. Education of patients and their families about signs and symptoms of possible drug interactions is also beneficial.

Pharmacokinetic Evaluation of CYP3A4‐Mediated Drug‐Drug Interactions of Isavuconazole With Rifampin, Ketoconazole, Midazolam, and Ethinyl Estradiol/Norethindrone in Healthy Adults

“…Accordingly, treatment recommendations generally indicate avoiding coadministration of these agents or increasing the dose of the triazole 9, 13. Isavuconazole is no exception, and coadministration of rifampin and isavuconazole is contraindicated.…”

Effects of Isavuconazole on the Plasma Concentrations of Tacrolimus among Solid-Organ Transplant Patients

“…Tacrolimus, a primary immunosuppressive agent in SOT, is a substrate of cytochrome P450 (CYP) 3A4. The triazole antifungals are CYP3A4 inhibitors that have varied effects on tacrolimus metabolism (2,3). The manufacturers of voriconazole and posaconazole recommend an empirical reduction of one-third in the daily tacrolimus dose; however, in clinical practice the required reduction is often substantially greater (4,5).…”

Pharmacokinetic Interactions Between Isavuconazole and the Drug Transporter Substrates Atorvastatin, Digoxin, Metformin, and Methotrexate in Healthy Subjects

“…Like most triazole antifungal agents,6 its active moiety, isavuconazole, is metabolized by the cytochrome P450 (CYP) system. Primarily, it is a sensitive substrate and acts as a moderate inhibitor of the CYP3A4 isoenzyme 9.…”