title: Fluconazole population pharmacokinetics and dosing for prevention and treatment of invasive Candidiasis in children supported with extracorporeal membrane oxygenation.
abstract: Candida infections are a leading cause of infectious disease-related death in children supported by extracorporeal membrane oxygenation (ECMO). The ECMO circuit can alter drug pharmacokinetics (PK); thus, standard fluconazole dosing may result in suboptimal drug exposures. The objective of our study was to determine the PK of fluconazole in children on ECMO. Forty children with 367 PK samples were included in the analysis. The PK data were analyzed using nonlinear mixed-effect modeling (NONMEM). A one-compartment model best described the data. Weight was included in the base model for clearance (CL) and volume of distribution (V). The final model included the effect of serum creatinine (SCR) level on CL and the effect of ECMO on V as follows: CL (in liters per hour) = 0.019 × weight × (SCR/0.4)(-0.29) × exp(ηCL) and V (in liters) = 0.93 × weight × 1.4(ECMO) × exp(ηV). The fluconazole V was increased in children supported by ECMO. Consequently, children on ECMO require a higher fluconazole loading dose for prophylaxis (12 mg/kg of body weight) and treatment (35 mg/kg) paired with standard maintenance doses to achieve exposures similar to those of children not on ECMO.
authors.affiliation: Department of Pediatrics, Duke University Medical Center, Durham, North Carolina, USA Duke Clinical Research Institute, Duke University Medical Center, Durham, North Carolina, USA Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina, USA.
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Watt
authors.affiliation: Duke Clinical Research Institute, Duke University Medical Center, Durham, North Carolina, USA Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Gonzalez
authors.affiliation: Department of Pediatrics, Duke University Medical Center, Durham, North Carolina, USA Duke Clinical Research Institute, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Daniel K
authors.initials: DK
authors.lastname: Benjamin
authors.affiliation: Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina, USA.
authors.forename: Kim L R
authors.initials: KL
authors.lastname: Brouwer
authors.affiliation: Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
authors.forename: Kelly C
authors.initials: KC
authors.lastname: Wade
authors.affiliation: Department of Pediatrics, University of California, San Diego, La Jolla, California, USA.
authors.forename: Edmund
authors.initials: E
authors.lastname: Capparelli
authors.affiliation: Division of Clinical Pharmacology and Therapeutics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Barrett
authors.affiliation: Department of Pediatrics, Duke University Medical Center, Durham, North Carolina, USA Duke Clinical Research Institute, Duke University Medical Center, Durham, North Carolina, USA michael.cohenwolkowiez@dm.duke.edu.
authors.forename: Michael
authors.initials: M
authors.lastname: Cohen-Wolkowiez
mesh_terms: D061605:Administration, Intravenous; D000293:Adolescent; D000935:Antifungal Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D001835:Body Weight; D058365:Candidiasis, Invasive / Q000188:drug therapy* / Q000517:prevention & control*; D002648:Child; D002675:Child, Preschool; D003404:Creatinine / Q000097:blood; D016638:Critical Illness; D004305:Dose-Response Relationship, Drug; D015199:Extracorporeal Membrane Oxygenation; D005260:Female; D015725:Fluconazole / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D015233:Models, Statistical; D011153:Population
chemical_list: D000935:Antifungal Agents; D015725:Fluconazole; D003404:Creatinine