title: Population Pharmacokinetic Model and Pharmacokinetic Target Attainment of Micafungin in Intensive Care Unit Patients.
abstract: To study the pharmacokinetics of micafungin in intensive care patients and assess pharmacokinetic (PK) target attainment for various dosing strategies.
  
  
  
  Micafungin PK data from 20 intensive care unit patients were available. A population-PK model was developed. Various dosing regimens were simulated: licensed regimens (I) 100 mg daily; (II) 100 mg daily with 200 mg from day 5; and adapted regimens 200 mg on day 1 followed by (III) 100 mg daily; (IV) 150 mg daily; and (V) 200 mg daily. Target attainment based on a clinical PK target for Candida as well as non-Candida parapsilosis infections was assessed for relevant minimum inhibitory concentrations [MICs] (Clinical and Laboratory Standards Institute). Parameter uncertainty was taken into account in simulations.
  
  
  
  A two-compartment model best fitted the data. Clearance was 1.10 (root square error 8%) L/h and V1and V2were 17.6 (root square error 14%) and 3.63 (root square error 8%) L, respectively. Median area under the concentration-time curve over 24 h (interquartile range) on day 14 for regimens I-V were 91 (67-122), 183 (135-244), 91 (67-122), 137 (101-183) and 183 (135-244) mg h/L, respectively, for a typical patient of 70 kg. For the MIC/area under the concentration-time curve >3000 target (all Candida spp.), PK target attainment was >91% on day 14 (MIC 0.016 mg/L epidemiological cut-off) for all of the dosing regimens but decreased to (I) 44%, (II) 91%, (III) 44%, (IV) 78% and (V) 91% for MIC 0.032 mg/L. For the MIC/area under the concentration-time curve >5000 target (non-C. parapsilosis spp.), PK target attainment varied between 62 and 96% on day 14 for MIC 0.016.
  
  
  
  The licensed micafungin maintenance dose results in adequate exposure based on our simulations with a clinical PK target for Candida infections but only 62% of patients reach the target for non-C. parapsilosis. In the case of pathogens with an attenuated micafungin MIC, patients may benefit from dose escalation to 200 mg daily. This encourages future study.
authors.affiliation: Department of Pharmacy, Radboud University Medical Center, P.O. Box 9101, Nijmegen, 6525 HB, The Netherlands.|The Netherlands Radboud Institute for Health Sciences, Nijmegen, The Netherlands.|Center of Expertise in Mycology, Radboud University Medical Center/CWZ, 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, Nijmegen, 6525 HB, The Netherlands.|The Netherlands Radboud Institute for Health Sciences, Nijmegen, The Netherlands.
authors.forename: Rob
authors.initials: R
authors.lastname: Ter Heine
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 and Pharmacy, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Nicole G
authors.initials: NG
authors.lastname: Hunfeld
authors.affiliation: Department of Intensive Care, Rijnstate Hospital, Arnhem, The Netherlands.
authors.forename: Henk J
authors.initials: HJ
authors.lastname: van Leeuwen
authors.affiliation: The Netherlands Radboud Institute for Health Sciences, Nijmegen, The Netherlands.|Center of Expertise in Mycology, Radboud University Medical Center/CWZ, 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 Intensive Care, University Medical Centre Utrecht, Utrecht, The Netherlands.
authors.forename: Dylan W
authors.initials: DW
authors.lastname: de Lange
authors.affiliation: Department of Intensive Care Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Peter
authors.initials: P
authors.lastname: Pickkers
authors.affiliation: Department of Pharmacy, Radboud University Medical Center, P.O. Box 9101, Nijmegen, 6525 HB, The Netherlands. roger.bruggemann@radboudumc.nl.|The Netherlands Radboud Institute for Health Sciences, Nijmegen, The Netherlands. roger.bruggemann@radboudumc.nl.|Center of Expertise in Mycology, Radboud University Medical Center/CWZ, Nijmegen, The Netherlands. roger.bruggemann@radboudumc.nl.
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Brüggemann
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000935:Antifungal Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D002175:Candida / Q000187:drug effects; D000074429:Candida parapsilosis / Q000187:drug effects; D002177:Candidiasis / Q000097:blood* / Q000188:drug therapy; D015331:Cohort Studies; D016503:Drug Delivery Systems / Q000379:methods*; D054714:Echinocandins / Q000008:administration & dosage / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D007362:Intensive Care Units / Q000639:trends; D055666:Lipopeptides / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008297:Male; D000077551:Micafungin; D008826:Microbial Sensitivity Tests / Q000379:methods; D008875:Middle Aged; D008954:Models, Biological; D009010:Monte Carlo Method; D011446:Prospective Studies; D055815:Young Adult
chemical_list: D000935:Antifungal Agents; D054714:Echinocandins; D055666:Lipopeptides; D000077551:Micafungin
keywords: Intensive Care Unit Patient; Invasive Candidiasis; Micafungin; Sequential Organ Failure Assessment; Sequential Organ Failure Assessment Score