Characterization of isavuconazole pharmacokinetics and pharmacodynamics in a real-life cohort

Objectives: Isavuconazole (ISA) is a triazole drug approved for the treatment of invasive aspergillosis and mucormycosis. Due to the relatively low interindividual variability of ISA pharmacokinetics and the lack of defined cutoffs for efficacy and toxicity, therapeutic drug monitoring (TDM) is rarely performed. This study aimed to characterize ISA pharmacokinetics and pharmacodynamics in real-life clinical settings and assess the potential role of TDM. Methods: We developed and validated a classical population pharmacokinetic (popPK) model using ISA concentrations obtained from patients undergoing TDM at three Swiss university hospitals. Additionally, we performed exploratory pharmacokinetic-pharmacodynamic analyses to investigate associations between ISA trough concentration or AUC, treatment outcomes, and hepatotoxicity using logistic regression models. Model-based simulations allowed assessing the role of TDM in clinical patient management. Results: A one-compartment model with interindividual variability in clearance best described our data. Among the covariates tested, only body mass index was found to influence the ISA volume of distribution to a clinically significant extent. Exposure-response analyses suggested a trend toward an association with treatment success, but not with toxicity. Model-based simulations show that TDM could increase the proportion of patients within the currently suggested ISA target ranges. Conclusion: Our results indicate that ISA exposure shows substantial variability and tends to correlate with outcome. This suggests a beneficial role for TDM in optimizing target achievement.