Caspofungin Population Pharmacokinetics in Critically Ill Patients Undergoing Continuous Veno-Venous Haemofiltration or Haemodiafiltration

Background and Objective Sepsis and continuous renal replacement therapy (CRRT) can both significantly affect antifungal pharmacokinetics. This study aimed to describe the pharmacokinetics of caspofungin in critically ill patients during different CRRT modes. Methods Patients receiving caspofungin and undergoing continuous veno-venous haemofiltration (CVVH) or haemodiafiltration (CVVHDF) were eligible to take part in the study. Blood samples were collected at seven sampling times during a dosing interval. Demographics and clinical data were recorded. Population pharmacokinetic analysis and Monte-Carlo simulation were undertaken using Pmetrics. Results Twelve pharmacokinetic profiles from nine patients were analysed. The caspofungin CRRT clearance (CL) was 0.048 ± 0.12 L/h for CVVH and 0.042 ± 0.042 L/h for CVVHDF. A two-compartment linear model best described the data. Patient weight was the only covariate affecting drug CL and central volume. The mean (standard deviation) parameter estimates were 0.64 ± 0.12 L/h for CL, 9.35 ± 3.56 L for central volume, 0.25 ± 0.19 per h for the rate constant for drug distribution from central to peripheral compartments and 0.19 ± 0.10 per h from peripheral to central compartments. Based on simulation results, a caspofungin 100 mg loading dose followed by a 50 mg maintenance dose for patients with a total body weight of ≤80 kg best achieved the pharmacokinetic/PD targets whilst a 70 mg maintenance dose was required for patients with a weight of >80 kg. Conclusion No caspofungin dosing adjustment is necessary for patients undergoing either form of CRRT. However, higher than recommended loading doses of caspofungin are required to achieve pharmacokinetic/pharmacodynamic targets in critically ill patients. Registration: ClinicalTrials.gov Identifier NCT01403220