title: Dose Reduction of Caspofungin in Intensive Care Unit Patients with Child Pugh B Will Result in Suboptimal Exposure.
abstract: Caspofungin is an echinocandin antifungal agent used as first-line therapy for the treatment of invasive candidiasis. The maintenance dose is adapted to body weight (BW) or liver function (Child-Pugh score B or C). We aimed to study the pharmacokinetics of caspofungin and assess pharmacokinetic target attainment for various dosing strategies.
  
  
  
  Caspofungin pharmacokinetic data from 21 intensive care unit (ICU) patients was available. A population pharmacokinetic model was developed. Various dosing regimens (loading dose/maintenance dose) were simulated: licensed regimens (I) 70/50 mg (for BW <80 kg) or 70/70 mg (for BW >80 kg); and (II) 70/35 mg (for Child-Pugh score B); and adapted regimens (III) 100/50 mg (for Child-Pugh score B); (IV) 100/70 mg; and (V) 100/100 mg. Target attainment based on a preclinical pharmacokinetic target for Candida albicans was assessed for relevant minimal inhibitory concentrations (MICs).
  
  
  
  A two-compartment model best fitted the data. Clearance was 0.55 L/h and the apparent volumes of distribution in the central and peripheral compartments were 8.9 and 5.0 L, respectively. The median area under the plasma concentration-time curve from time zero to 24 h on day 14 for regimens I-V were 105, 65, 93, 130, and 186 mg·h/L, respectively. Pharmacokinetic target attainment was 100 % (MIC 0.03 µg/mL) irrespective of dosing regimen but decreased to (I) 47 %, (II) 14 %, (III) 36 %, (IV) 69 %, and (V) 94 % for MIC 0.125 µg/mL.
  
  
  
  The caspofungin maintenance dose should not be reduced in non-cirrhotic ICU patients based on the Child-Pugh score if this classification is driven by hypoalbuminemia as it results in significantly lower exposure. A higher maintenance dose of 70 mg in ICU patients results in target attainment of >90 % of the ICU patients with species with an MIC of up to 0.125 µg/mL.
authors.affiliation: Department of Pharmacy, Radboud university medical center, P.O. Box 9101, 6525 HB, Nijmegen, The Netherlands.|Radboud Institute for Health Sciences, Nijmegen, The Netherlands.
authors.forename: Lisa C
authors.initials: LC
authors.lastname: Martial
authors.affiliation: Department of Pharmacy, Radboud university medical center, P.O. Box 9101, 6525 HB, Nijmegen, The Netherlands. roger.bruggemann@radboudumc.nl.|Radboud Institute for Health Sciences, Nijmegen, The Netherlands. roger.bruggemann@radboudumc.nl.
authors.forename: Roger J M
authors.initials: RJ
authors.lastname: Brüggemann
authors.affiliation: Department of Intensive Care, Canisius Wilhelmina Hospital, Nijmegen, The Netherlands.
authors.forename: Jeroen A
authors.initials: JA
authors.lastname: Schouten
authors.affiliation: Department of Intensive Care, Rijnstate Hospital, Arnhem, The Netherlands.
authors.forename: Henk J
authors.initials: HJ
authors.lastname: van Leeuwen
authors.affiliation: Department of Intensive Care, Gelderse Vallei Hospital, Ede, The Netherlands.
authors.forename: Arthur R
authors.initials: AR
authors.lastname: van Zanten
authors.affiliation: Department of Intensive Care and National Poison Information Center Utrecht, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Dylan W
authors.initials: DW
authors.lastname: de Lange
authors.affiliation: Department of Pharmacy, Radboud university medical center, P.O. Box 9101, 6525 HB, Nijmegen, The Netherlands.|Radboud Institute for Health Sciences, Nijmegen, The Netherlands.
authors.forename: Eline W
authors.initials: EW
authors.lastname: Muilwijk
authors.affiliation: Radboud Institute for Health Sciences, Nijmegen, The Netherlands.|Department of Medical Microbiology, Radboud university medical center, Nijmegen, The Netherlands.
authors.forename: Paul E
authors.initials: PE
authors.lastname: Verweij
authors.affiliation: Department of Pharmacy, Radboud university medical center, P.O. Box 9101, 6525 HB, Nijmegen, The Netherlands.|Radboud Institute for Health Sciences, Nijmegen, The Netherlands.
authors.forename: David M
authors.initials: DM
authors.lastname: Burger
authors.affiliation: Department of Pharmacy, Radboud university medical center, P.O. Box 9101, 6525 HB, Nijmegen, The Netherlands.|Radboud Institute for Health Sciences, Nijmegen, The Netherlands.
authors.forename: Rob E
authors.initials: RE
authors.lastname: Aarnoutse
authors.affiliation: Department of Intensive Care, Radboud university medical center, Nijmegen, The Netherlands.
authors.forename: Peter
authors.initials: P
authors.lastname: Pickkers
authors.affiliation: Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.|Division of Pharmacoepidemiology and Clinical Pharmacology, Faculty of Science, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, Utrecht, The Netherlands.
authors.forename: Thomas P C
authors.initials: TP
authors.lastname: Dorlo
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000935:Antifungal Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D015992:Body Mass Index; D002177:Candidiasis / Q000188:drug therapy*; D000077336:Caspofungin; D004305:Dose-Response Relationship, Drug; D054714:Echinocandins / Q000008:administration & dosage* / Q000627:therapeutic use; D005260:Female; D006801:Humans; D007362:Intensive Care Units; D055666:Lipopeptides / Q000008:administration & dosage* / Q000627:therapeutic use; D008297:Male; D008657:Metabolic Clearance Rate; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D008954:Models, Biological; D009010:Monte Carlo Method; D012720:Severity of Illness Index; D055815:Young Adult
chemical_list: D000935:Antifungal Agents; D054714:Echinocandins; D055666:Lipopeptides; D000077336:Caspofungin