title: Caspofungin Population Pharmacokinetics in Critically Ill Patients Undergoing Continuous Veno-Venous Haemofiltration or Haemodiafiltration.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Service des Réanimations, Pôle Anesthésie Réanimation Douleur Urgence, CHU Nîmes, Nîmes, France. claire.roger@chu-nimes.fr.|Burns, Trauma, and Critical Care Research Centre, The University of Queensland, Brisbane, QLD, Australia. claire.roger@chu-nimes.fr.
authors.forename: Claire
authors.initials: C
authors.lastname: Roger
authors.affiliation: Burns, Trauma, and Critical Care Research Centre, The University of Queensland, Brisbane, QLD, Australia.
authors.forename: Steven C
authors.initials: SC
authors.lastname: Wallis
authors.affiliation: Service des Réanimations, Pôle Anesthésie Réanimation Douleur Urgence, CHU Nîmes, Nîmes, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Muller
authors.affiliation: Service des Réanimations, Pôle Anesthésie Réanimation Douleur Urgence, CHU Nîmes, Nîmes, France.
authors.forename: Gilbert
authors.initials: G
authors.lastname: Saissi
authors.affiliation: Burns, Trauma, and Critical Care Research Centre, The University of Queensland, Brisbane, QLD, Australia.|School of Pharmacy, The University of Queensland, Brisbane, QLD, Australia.|Department of Intensive Care Medicine, Royal Brisbane and Womens' Hospital, Brisbane, QLD, Australia.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Lipman
authors.affiliation: Department of Pharmacy, Radboud University Medical Center, Nijmegen, The Netherlands.|Center of Expertise in Mycology Radboudumc/CWZ, Nijmegen, The Netherlands.|Radboud Institute of Health Science, Nijmegen, The Netherlands.
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Brüggemann
authors.affiliation: Service des Réanimations, Pôle Anesthésie Réanimation Douleur Urgence, CHU Nîmes, Nîmes, France.
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Lefrant
authors.affiliation: Burns, Trauma, and Critical Care Research Centre, The University of Queensland, Brisbane, QLD, Australia.|School of Pharmacy, The University of Queensland, Brisbane, QLD, Australia.|Department of Intensive Care Medicine, Royal Brisbane and Womens' Hospital, Brisbane, QLD, Australia.|Pharmacy Department, Royal Brisbane and Womens' Hospital, Brisbane, QLD, Australia.
authors.forename: Jason A
authors.initials: JA
authors.lastname: Roberts
mesh_terms: D000368:Aged; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D000935:Antifungal Agents / Q000493:pharmacokinetics / Q000627:therapeutic use; D000077336:Caspofungin; D016638:Critical Illness / Q000628:therapy; D054714:Echinocandins / Q000493:pharmacokinetics / Q000627:therapeutic use; D017583:Hemodiafiltration / Q000639:trends; D006440:Hemofiltration / Q000639:trends; D055666:Lipopeptides / Q000493:pharmacokinetics / Q000627:therapeutic use; D008657:Metabolic Clearance Rate / Q000187:drug effects / Q000502:physiology; D008826:Microbial Sensitivity Tests / Q000639:trends
chemical_list: D000935:Antifungal Agents; D000077336:Caspofungin; D054714:Echinocandins; D055666:Lipopeptides
keywords: Caspofungin; Continuous Renal Replacement Therapy; Intensive Care Unit Patient; Sequential Organ Failure Assessment; Total Body Weight