Suboptimal concentrations of isavuconazole in critically ill patients treated for mold infections: a population pharmacokinetic analysis

Isavuconazole is approved for first-line treatment of aspergillosis, including COVID-19-associated pulmonary aspergillosis, and as an alternative for mucormycosis. However, its use in intensive care units (ICU) is not well characterized. We developed a population pharmacokinetic (popPK) model using 134 isavuconazole plasma concentrations retrospectively collected from 22 ICU patients over four years. Monte Carlo simulations were performed to optimize dosing strategies for rapid and maximal isavuconazole exposure. Diagnoses included suspected or probable aspergillosis (n = 17) and mucormycosis (n = 3). During the first 10 days of treatment, one-third of observed trough concentrations were below the target of 1 mg/L. A two-compartment model best estimated pharmacokinetic parameters, with no significant covariates identified to explain high variability. Simulations indicated that the standard dosing regimen (200 mg q8h for 2 days, then 200 mg qd) would not achieve the targeted area under the concentration-time curve during a 24-hour period to the minimal inhibitory concentration ratio of 33.34 mg/L in 45% of patients during the first ten days. Conversely, a loading dose of 400 mg q8h followed by a maintenance dose of 400 mg qd achieved the target in over 80% of patients. Isavuconazole exposure in the ICU was suboptimal with high pharmacokinetic variability. Pending external validation, isavuconazole concentrations should be monitored, and higher dosing regimens considered at treatment initiation.