Abstract
Introduction: Isavuconazole is an antifungal agent recently recommended as first-line therapy for invasive pulmonary aspergillosis. With the COVID-19 pandemic, cases of COVID-19-associated pulmonary aspergillosis (CAPA) have been described with a prevalence ranging from 5% to 30% [1,2]. The expert panel recommended either voriconazole or isavuconazole as first-line treatment for possible, probable, or proven CAPA [3].Material and methods: We developed and validated a population pharmacokinetic (PKpop) model of isavuconazole plasma concentrations in intensive care unit patients with CAPA. Nonlinear mixed-effect modeling Monolix software were used for PK analysis of 65 plasma trough concentrations from 18 patients. Three off-label dosing regimens were simulated by SimulX.Results: The mean of isavuconazole plasma concentrations was 1.87 [1.29–2.25] mg/L despite prolonged loading dose (72 h for one-third) and a mean maintenance dose of 300 mg per day. PK parameters were best estimated with a one-compartment model. Pharmacokinetics (PK) modeling showed that renal replacement therapy (RRT) was significantly associated with under exposure explaining a part of clearance variability. From the final model, Monte Carlo simulations were performed to determine the optimal dosing regimen in our population to achieve a target concentration of 2 mg/L at 72 h and 7 days. The off-label regimen with a loading dose of 800 mg/day over 72 h and a maintenance dose of 400 mg achieved the target in 69% and 57% of cases at 72 h and 94% and 72% at 7 days for non-RRT and RRT patients, respectively.Discussion/Conclusion: This is the first isavuconazole PKpop model developed for CAPA critical care patients underlying the need of therapeutic drug monitoring, especially for patients under RRT. Our data suggest that, in these ICU patients for whom ensuring effective exposure as quickly as possible is a major issue, a dosing regimen higher than that recommended (LD 48 h 600 mg/day and MD 200 mg/day) could be proposed.References:[1] Bartoletti M et al. Epidemiology of invasive pulmonary aspergillosis among COVID-19 intubated patients: a prospective study. Clin Infect Dis 2020, ciaa1065.[2] Lahmer T et al. Invasive pulmonary aspergillosis in critically ill patients with severe COVID-19 pneumonia: results from the prospective AspCOVID-19 study. PLoS One 2021, 16, e0238825.[3] Koehler P et al. Defining and managing COVID-19-associated pulmonary aspergillosis: the 2020 ECMM/ISHAM consensus criteria for research and clinical guidance. Lancet Infect Dis 2021, 21, e149–e162.