title: Pharmacokinetics and safety of fluconazole in young infants supported with extracorporeal membrane oxygenation.
abstract: BACKGROUND
  Candida infections are a leading cause of infectious disease-related death in infants supported with extracorporeal membrane oxygenation (ECMO). The ECMO circuit can alter drug pharmacokinetics; thus, standard fluconazole dosing in children on ECMO may result in suboptimal drug exposure. This study determined the pharmacokinetics of fluconazole in infants on ECMO.
  
  
  METHODS
  Infants <120 days of age received either intravenous fluconazole prophylaxis (25 mg/kg once a week) or treatment (12 mg/kg daily) while on ECMO. Paired plasma samples were collected preoxygenator and postoxygenator around doses 1 and 2 to calculate pharmacokinetic indices and describe oxygenator extraction. A 1-compartment model was fit to the data using nonlinear regression. Surrogate pharmacodynamic targets for efficacy were evaluated.
  
  
  RESULTS
  Ten infants were enrolled. After dose 1 (n = 9), the median clearance was 17 mL/kg/h, the median volume of distribution was 1.5 L/kg and the median exposure in the first 24 hours (area under the curve from 0 to 24 hours) was 322 h × mg/L. After multiple doses (n = 7), the median clearance was 22 mL/kg/h, the median volume of distribution was 1.9 L/kg and the area under the curve from 0 to 24 hours was 352 h × mg/L. After dose 1, 78% of infants achieved the prophylaxis target, whereas only 11% achieved the therapeutic target. Oxygenator extraction of fluconazole was minimal (-2.0%, standard deviation 15.0), and extraction was not correlated with age of the ECMO circuit (ρ= -0.05). There were no adverse events related to fluconazole.
  
  
  CONCLUSIONS
  Infants on ECMO had higher volume of distribution but similar clearance when compared with historical controls not on ECMO. In infants on ECMO, a fluconazole dose of 25 mg/kg weekly provides adequate exposure for prophylaxis against Candida infections. However, higher doses may be needed for treatment.
authors.affiliation: Duke University, Pediatrics, Duke Clinical Research Institute, P.O. Box 3499, Durham, NC 27710, USA.
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Watt
authors.forename: Daniel K
authors.initials: DK
authors.lastname: Benjamin
authors.forename: Ira M
authors.initials: IM
authors.lastname: Cheifetz
authors.forename: Ganesh
authors.initials: G
authors.lastname: Moorthy
authors.forename: Kelly C
authors.initials: KC
authors.lastname: Wade
authors.forename: P Brian
authors.initials: PB
authors.lastname: Smith
authors.forename: Kim L R
authors.initials: KL
authors.lastname: Brouwer
authors.forename: Edmund V
authors.initials: EV
authors.lastname: Capparelli
authors.forename: Michael
authors.initials: M
authors.lastname: Cohen-Wolkowiez
mesh_terms: D000935:Antifungal Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D002177:Candidiasis / Q000188:drug therapy* / Q000517:prevention & control*; D018890:Chemoprevention / Q000379:methods; D015199:Extracorporeal Membrane Oxygenation / Q000009:adverse effects*; D005260:Female; D015725:Fluconazole / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007262:Infusions, Intravenous; D008297:Male; D008657:Metabolic Clearance Rate; D010949:Plasma / Q000737:chemistry; D011446:Prospective Studies
chemical_list: D000935:Antifungal Agents; D015725:Fluconazole