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Pharmacokinetics and safety of fluconazole in young infants supported with extracorporeal membrane oxygenation.

Publication ,  Journal Article
Watt, KM; Benjamin, DK; Cheifetz, IM; Moorthy, G; Wade, KC; Smith, PB; Brouwer, KLR; Capparelli, EV; Cohen-Wolkowiez, M
Published in: Pediatr Infect Dis J
October 2012

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.

Duke Scholars

Published In

Pediatr Infect Dis J

DOI

EISSN

1532-0987

Publication Date

October 2012

Volume

31

Issue

10

Start / End Page

1042 / 1047

Location

United States

Related Subject Headings

  • Prospective Studies
  • Plasma
  • Pediatrics
  • Metabolic Clearance Rate
  • Male
  • Infusions, Intravenous
  • Infant, Newborn
  • Infant
  • Humans
  • Fluconazole
 

Citation

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ICMJE
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Watt, K. M., Benjamin, D. K., Cheifetz, I. M., Moorthy, G., Wade, K. C., Smith, P. B., … Cohen-Wolkowiez, M. (2012). Pharmacokinetics and safety of fluconazole in young infants supported with extracorporeal membrane oxygenation. Pediatr Infect Dis J, 31(10), 1042–1047. https://doi.org/10.1097/INF.0b013e31825d3091
Watt, Kevin M., Daniel K. Benjamin, Ira M. Cheifetz, Ganesh Moorthy, Kelly C. Wade, P Brian Smith, Kim L. R. Brouwer, Edmund V. Capparelli, and Michael Cohen-Wolkowiez. “Pharmacokinetics and safety of fluconazole in young infants supported with extracorporeal membrane oxygenation.Pediatr Infect Dis J 31, no. 10 (October 2012): 1042–47. https://doi.org/10.1097/INF.0b013e31825d3091.
Watt KM, Benjamin DK, Cheifetz IM, Moorthy G, Wade KC, Smith PB, et al. Pharmacokinetics and safety of fluconazole in young infants supported with extracorporeal membrane oxygenation. Pediatr Infect Dis J. 2012 Oct;31(10):1042–7.
Watt, Kevin M., et al. “Pharmacokinetics and safety of fluconazole in young infants supported with extracorporeal membrane oxygenation.Pediatr Infect Dis J, vol. 31, no. 10, Oct. 2012, pp. 1042–47. Pubmed, doi:10.1097/INF.0b013e31825d3091.
Watt KM, Benjamin DK, Cheifetz IM, Moorthy G, Wade KC, Smith PB, Brouwer KLR, Capparelli EV, Cohen-Wolkowiez M. Pharmacokinetics and safety of fluconazole in young infants supported with extracorporeal membrane oxygenation. Pediatr Infect Dis J. 2012 Oct;31(10):1042–1047.

Published In

Pediatr Infect Dis J

DOI

EISSN

1532-0987

Publication Date

October 2012

Volume

31

Issue

10

Start / End Page

1042 / 1047

Location

United States

Related Subject Headings

  • Prospective Studies
  • Plasma
  • Pediatrics
  • Metabolic Clearance Rate
  • Male
  • Infusions, Intravenous
  • Infant, Newborn
  • Infant
  • Humans
  • Fluconazole