Population Pharmacokinetics of Isavuconazole in Critical Care Patients with COVID-19-Associated Pulmonary Aspergillosis and Monte Carlo Simulations of High Off-Label Doses

Abstract

Isavuconazole is a triazole 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%. 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. PK parameters were best estimated with a one-compartment model. The mean of ISA 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. Pharmacokinetics (PK) modeling showed that renal replacement therapy (RRT) was significantly associated with under exposure, explaining a part of clearance variability. The Monte Carlo simulations suggested that the recommended dosing regimen did not achieve the trough target of 2 mg/L in a timely manner (72 h). 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.

Isavuconazole Pharmacokinetics in Critically Ill Patients: Relationship with Clinical Effectiveness and Patient Safety

“…None of these factors were relevant for our patient's isavuconazole Pk, and were excluded in our compartmental model. Although isavuconazole oral administration seems to be better studied by bi-compartimental model, previous publications agreed with our mono-compartmental model in intravenous administration [19]. Moreover, Perez et al´s model only found CRRT as a signi cant covariant for isavuconazole Pk in 18 critically ill patients [19].…”

“…Although there is no total consensus about the normal range in isavuconazole trough concentrations, most authors accept a range between 1 and 5 mg/L [3,[19][20][21]. Population pharmacokinetic parameters were performed from the plasma concentrations obtained and using the computer software NONMEN® (v.5) implementing a rst-order conditional estimation method with interaction (ADVAN 1, TRANS 2).…”

“…The limited number of studies on isavuconazole Pk in critical care patients has shown inconsistent results [12][13][14]. Impaired renal or hepatic function, continuous renal replacement therapy (CRRT) or extracorporeal membrane oxygenation (ECMO) make drug concentrations prediction di cult, and thus, TDM could be necessary in this population [15][16][17][18][19].…”

Clinical and demographic factors affecting trough levels of isavuconazole in critically ill patients with or without COVID‐19

“…A number of studies have analysed isavuconazole drug levels in different patient populations or with specific risk factors. Whereas numerous of those support the use of routine TDM of isavuconazole, 15,16 some reports question this measure, 17 but acknowledge its value under specific circumstances.…”

“…32,33 Regarding the influence of RRT on isavuconazole levels, a study with seven solid-organ transplant patients reported no rapid removal by RRT, 34 while others found an association between RRT and sub-therapeutic levels of the drug. 15,16,30,35 The role of adsorptive membranes has been related to lowered maximal concentrations of echinocandins, which are similarly lipophilic like isavuconazole. 36 Therefore, the adsorption of isavuconazole to the synthetic surfaces of hemofilters could contribute to the decreased drug levels in RRT patients.…”