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

Abstract

Background Isavuconazole is a new drug used to treat fungal infections. This study aims to describe isavuconazole pharmacokinetics in critically ill patients, assess the potential influence of patient covariates, and evaluate the relationship with clinical efficacy and patient safety. Methods We conducted a prospective, observational study in critically ill patients treated with intravenous isavuconazole for at least 48 hours. Samples were collected between 48–96 hours of onset of treatment, at predose (Cmin), 1 hour (Cmax) and 12 hours (C50) after last dose. Plasma concentration was determined by a high-performance liquid chromatography with fluorescence detector. The relationship between plasma concentration and clinical and microbiological outcome, and safety was evaluated. The influence of covariates such as age, sex, weight, SAPS3, creatinine, bilirubin, liver enzymes and extracorporeal devices (continuous re-emplace renal therapy (CRRT) and extracorporeal membrane oxygenation (ECMO)) was analysed. Population pharmacokinetic modelling was performed using NONMEN®. Results A total of 71 isavuconazole samples from 24 patients were analysed. Mean Cmin was 1.76 (1.02) mg/L. Twenty-one patients (87.5%) reached the optimal therapeutic target, while three patients (12.5%) were below 1 mg/L. Population pharmacokinetic was best described by a one-compartimental model with first-order elimination. No factor, including CRRT or ECMO support, had a significantly impact on plasma concentration or pharmacokinetic parameters. No relationship was observed between isavuconazole plasma level and clinical effectiveness or adverse event appearance. Conclusions Isavuconazole use in critically ill patients at established doses was accompanied by plasma levels within the therapeutic range. This pharmacokinetic confidence remained independent of demographic, clinical, or therapeutic factors and did not affect the drug´s efficacy and safety.