title: Altered Micafungin Pharmacokinetics in Intensive Care Unit Patients.
abstract: Micafungin is considered an important agent for the treatment of invasive fungal infections in the intensive care unit (ICU). Little is known on the pharmacokinetics of micafungin. We investigated micafungin pharmacokinetics (PK) in ICU patients and set out to explore the parameters that influence micafungin plasma concentrations. ICU patients receiving 100 mg of intravenous micafungin once daily for suspected or proven fungal infection or as prophylaxis were eligible. Daily trough concentrations and PK curves (days 3 and 7) were collected. Pharmacokinetic analysis was performed using a standard two-stage approach. Twenty patients from the ICUs of four hospitals were evaluated. On day 3 (n = 20), the median (interquartile range [IQR]) area under the concentration-time curve from 0 to 24 h (AUC0-24) was 78.6 (65.3 to 94.1) mg · h/liter, the maximum concentration of drug in serum (Cmax) was 7.2 (5.4 to 9.2) mg/liter, the concentration 24 h after dosing (C24) was 1.55 (1.4 to 3.1) mg/liter, the volume of distribution (V) was 25.6 (21.3 to 29.1) liters, the clearance (CL) was 1.3 (1.1 to 1.5) liters/h, and the elimination half-life (t1/2) was 13.7 (12.2 to 15.5) h. The pharmacokinetic parameters on day 7 (n = 12) were not significantly different from those on day 3. Daily trough concentrations (day 3 to the end of therapy) showed moderate interindividual (57.9%) and limited intraindividual variability (12.9%). No covariates of the influence on micafungin exposure were identified. Micafungin was considered safe and well tolerated. We performed the first PK study with very intensive sampling on multiple occasions in ICU patients, which aided in resolving micafungin PK. Strikingly, micafungin exposure in our cohort of ICU patients was lower than that in healthy volunteers but not significantly different from that of other reference populations. The clinical consequence of these findings must be investigated in a pharmacokinetic-pharmacodynamic (PK-PD) study incorporating outcome in a larger cohort. (This study is registered at ClinicalTrials.gov under registration no. NCT01783379.).
authors.affiliation: Radboud University Medical Center, Department of Pharmacy, Nijmegen, The Netherlands Radboud Institute for Health Sciences, Nijmegen, The Netherlands.
authors.forename: Vincent J
authors.initials: VJ
authors.lastname: Lempers
authors.affiliation: Canisius Wilhelmina Hospital, Department of Intensive Care, Nijmegen, The Netherlands.
authors.forename: Jeroen A
authors.initials: JA
authors.lastname: Schouten
authors.affiliation: Erasmus Medical Center, Department of Intensive Care, Rotterdam, The Netherlands.
authors.forename: Nicole G
authors.initials: NG
authors.lastname: Hunfeld
authors.affiliation: Radboud University Medical Center, Department of Pharmacy, Nijmegen, The Netherlands Radboud Institute for Health Sciences, Nijmegen, The Netherlands.
authors.forename: Angela
authors.initials: A
authors.lastname: Colbers
authors.affiliation: Rijnstate Hospital, Department of Intensive Care, Arnhem, The Netherlands.
authors.forename: Henk J
authors.initials: HJ
authors.lastname: van Leeuwen
authors.affiliation: Radboud University Medical Center, Department of Pharmacy, Nijmegen, The Netherlands Radboud Institute for Health Sciences, Nijmegen, The Netherlands.
authors.forename: David M
authors.initials: DM
authors.lastname: Burger
authors.affiliation: Radboud Institute for Health Sciences, Nijmegen, The Netherlands Radboud University Medical Center, Department of Medical Microbiology, Nijmegen, The Netherlands.
authors.forename: Paul E
authors.initials: PE
authors.lastname: Verweij
authors.affiliation: Radboud University Medical Center, Department of Intensive Care, Nijmegen, The Netherlands.
authors.forename: Peter
authors.initials: P
authors.lastname: Pickkers
authors.affiliation: Radboud University Medical Center, Department of Pharmacy, Nijmegen, The Netherlands Radboud Institute for Health Sciences, Nijmegen, The Netherlands roger.bruggemann@radboudumc.nl.
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Brüggemann
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000935:Antifungal Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019540:Area Under Curve; D003422:Critical Care / Q000379:methods; D004334:Drug Administration Schedule; D054714:Echinocandins / Q000008:administration & dosage / Q000493:pharmacokinetics*; D005260:Female; D006207:Half-Life; D006801:Humans; D007362:Intensive Care Units; D055666:Lipopeptides / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008297:Male; D000077551:Micafungin; D008875:Middle Aged; D009181:Mycoses / Q000188:drug therapy; D055815:Young Adult
chemical_list: D000935:Antifungal Agents; D054714:Echinocandins; D055666:Lipopeptides; D000077551:Micafungin