Non-stationary Pharmacokinetics of Caspofungin in ICU Patients

Antimicrob Agents Chemother. 2020 Jun 29;AAC.00345-20. doi: 10.1128/AAC.00345-20. Online ahead of print.

Abstract

Standard dosing of caspofungin in critically ill patients has been reported to result in lower drug exposure, which can lead to subtherapeutic AUC0-24/MIC ratios. The aim of the study was to investigate the population pharmacokinetics of caspofungin in a cohort of 30 ICU patients with a suspected invasive fungal infection, with a large proportion of patients requiring extracorporeal therapies including ECMO and CRRT. Caspofungin was administered as empirical antifungal therapy 70 mg i.v. on the first day and 50 mg i.v. on the consecutive days once daily and the concentrations were measured after 3 subsequent doses. Population pharmacokinetic data were analysed by nonlinear mixed-effects modeling. The pharmacokinetics of caspofungin was described by 2-compartment model. A particular drift of individual CL and V1 values with time was discovered and described by including three separate typical values of CL and V1 in the final model. The typical CL values at day one, two and three were 0.563 L/h (6.7 %RSE), 0.737 L/h (6.1 %RSE) and 1.01 L/h (9.1 %RSE), respectively. The change in parameters with time was not explained by any of the recorded covariates. Increasing clearance with subsequent doses was associated with a clinically relevant decrease in caspofungin exposure (>20%). The use of ECMO, CRRT, albumin concentration, and other covariates did not significantly affect caspofungin pharmacokinetics. Additional pharmacokinetic studies are urgently required to assess the possible lack of acquiring steady-state and suboptimal concentrations of the drug in critically ill patients.