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Antimicrob Agents Chemother. 2015 Jul;59(7):3935-43. doi: 10.1128/AAC.00102-15. Epub 2015 Apr 20.

Fluconazole population pharmacokinetics and dosing for prevention and treatment of invasive Candidiasis in children supported with extracorporeal membrane oxygenation.

Author information

1
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.
2
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.
3
Department of Pediatrics, Duke University Medical Center, Durham, North Carolina, USA Duke Clinical Research Institute, Duke University Medical Center, Durham, North Carolina, USA.
4
Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina, USA.
5
Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
6
Department of Pediatrics, University of California, San Diego, La Jolla, California, USA.
7
Division of Clinical Pharmacology and Therapeutics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
8
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.

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.

PMID:
25896706
PMCID:
PMC4468733
DOI:
10.1128/AAC.00102-15
[Indexed for MEDLINE]
Free PMC Article

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