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Physiologically Based Pharmacokinetic Approach to Determine Dosing on Extracorporeal Life Support: Fluconazole in Children on ECMO.

Publication ,  Journal Article
Watt, KM; Cohen-Wolkowiez, M; Barrett, JS; Sevestre, M; Zhao, P; Brouwer, KLR; Edginton, AN
Published in: CPT Pharmacometrics Syst Pharmacol
October 2018

Extracorporeal life support (e.g., dialysis, extracorporeal membrane oxygenation (ECMO)) can affect drug disposition, placing patients at risk for therapeutic failure. In this population, dose selection to achieve safe and effective drug exposure is difficult. We developed a novel and flexible approach that uses physiologically based pharmacokinetic (PBPK) modeling to translate results from ECMO ex vivo experiments into bedside dosing recommendations. To determine fluconazole dosing in children on ECMO, we developed a PBPK model, which was validated using fluconazole pharmacokinetic (PK) data in adults and critically ill infants. Next, an ECMO compartment was added to the PBPK model and parameterized using data from a previously published ex vivo study. Simulations using the final ECMO PBPK model reasonably characterized observed PK data in infants on ECMO, and the model was used to derive dosing in children on ECMO across the pediatric age spectrum. This approach can be generalized to other forms of extracorporeal life support (ECLS), such as dialysis.

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Published In

CPT Pharmacometrics Syst Pharmacol

DOI

EISSN

2163-8306

Publication Date

October 2018

Volume

7

Issue

10

Start / End Page

629 / 637

Location

United States

Related Subject Headings

  • Models, Biological
  • Male
  • Humans
  • Fluconazole
  • Extracorporeal Membrane Oxygenation
  • Dose-Response Relationship, Drug
  • Child
  • Candidiasis
  • Area Under Curve
  • Antifungal Agents
 

Citation

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Watt, K. M., Cohen-Wolkowiez, M., Barrett, J. S., Sevestre, M., Zhao, P., Brouwer, K. L. R., & Edginton, A. N. (2018). Physiologically Based Pharmacokinetic Approach to Determine Dosing on Extracorporeal Life Support: Fluconazole in Children on ECMO. CPT Pharmacometrics Syst Pharmacol, 7(10), 629–637. https://doi.org/10.1002/psp4.12338
Watt, Kevin M., Michael Cohen-Wolkowiez, Jeffrey S. Barrett, Michael Sevestre, Ping Zhao, Kim L. R. Brouwer, and Andrea N. Edginton. “Physiologically Based Pharmacokinetic Approach to Determine Dosing on Extracorporeal Life Support: Fluconazole in Children on ECMO.CPT Pharmacometrics Syst Pharmacol 7, no. 10 (October 2018): 629–37. https://doi.org/10.1002/psp4.12338.
Watt KM, Cohen-Wolkowiez M, Barrett JS, Sevestre M, Zhao P, Brouwer KLR, et al. Physiologically Based Pharmacokinetic Approach to Determine Dosing on Extracorporeal Life Support: Fluconazole in Children on ECMO. CPT Pharmacometrics Syst Pharmacol. 2018 Oct;7(10):629–37.
Watt, Kevin M., et al. “Physiologically Based Pharmacokinetic Approach to Determine Dosing on Extracorporeal Life Support: Fluconazole in Children on ECMO.CPT Pharmacometrics Syst Pharmacol, vol. 7, no. 10, Oct. 2018, pp. 629–37. Pubmed, doi:10.1002/psp4.12338.
Watt KM, Cohen-Wolkowiez M, Barrett JS, Sevestre M, Zhao P, Brouwer KLR, Edginton AN. Physiologically Based Pharmacokinetic Approach to Determine Dosing on Extracorporeal Life Support: Fluconazole in Children on ECMO. CPT Pharmacometrics Syst Pharmacol. 2018 Oct;7(10):629–637.
Journal cover image

Published In

CPT Pharmacometrics Syst Pharmacol

DOI

EISSN

2163-8306

Publication Date

October 2018

Volume

7

Issue

10

Start / End Page

629 / 637

Location

United States

Related Subject Headings

  • Models, Biological
  • Male
  • Humans
  • Fluconazole
  • Extracorporeal Membrane Oxygenation
  • Dose-Response Relationship, Drug
  • Child
  • Candidiasis
  • Area Under Curve
  • Antifungal Agents