DDMODEL00000304: Executable_Simulated_FluconazolePretermInfantPBPK

  public model
Short description:
A Physiologically-Based Pharmacokinetic (PBPK) Model of Fluconazole Using Plasma and Cerebrospinal Fluid Samples From Preterm and Term Infants
Original code
  • Physiologically-Based Pharmacokinetic Modeling of Fluconazole Using Plasma and Cerebrospinal Fluid Samples From Preterm and Term Infants.
  • Gerhart JG, Watt KM, Edginton A, Wade KC, Salerno SN, Benjamin DK Jr, Smith PB, Hornik CP, Cohen-Wolkowiez M, Duara S, Ross A, Shattuck K, Stewart DL, Neu N, Gonzalez D
  • CPT: pharmacometrics & systems pharmacology, 7/2019, Volume 8, Issue 7, pages: 500-510
  • Division of Pharmacotherapy and Experimental Therapeutics, University of North Carolina Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
  • Fluconazole is used to treat hematogenous Candida meningoencephalitis in preterm and term infants. To characterize plasma and central nervous system exposure, an adult fluconazole physiologically-based pharmacokinetic (PBPK) model was scaled to infants, accounting for age dependencies in glomerular filtration and metabolism. The model was optimized using 760 plasma samples from 166 infants (median postmenstrual age (range) 28 weeks (24-50)) and 27 cerebrospinal fluid (CSF) samples from 22 infants (postmenstrual age 28 weeks (24-33)). Simulations evaluated achievement of the surrogate efficacy target of area under the unbound concentration-time curve ? 400 mg • hour/L over the dosing interval in plasma and CSF using dosing guidelines. Average fold error of predicted concentrations was 0.73 and 1.14 for plasma and CSF, respectively. Target attainment in plasma and CSF was reached faster after incorporating a loading dose of 25 mg/kg. PBPK modeling can be useful in exploring CNS kinetics of drugs in children.
Jacqueline Gerhart
Context of model development: Dose & Schedule Selection and Label Recommendation;
Discrepancy between implemented model and original publication: For demonstration purposes, the 'observed' data in the Executable_FluconazolePretermInfantPBPK.pksim5 file were randomly sampled from the population simulation results. Four hundred plasma samples and 100 CSF samples from virtual infants in the virtual population were randomly selected from any time point within the full dosing interval. Using this simulated practice data allowed for showing the parameter estimation of the GFR fraction parameter. Optimization using the simulated practice data yielded a GFR fraction of 0.35, which is close to the actual final model value of 0.30 when optimizing using the actual observed Prophylaxis Study data. Actual observed data for model development and evaluation could not be included in this repository posting as it is only accessible through a data use agreement.For demonstration purposes, the 'observed' data in the Executable_FluconazolePretermInfantPBPK.pksim5 file were randomly sampled from the population simulation results. Four hundred plasma samples and 100 CSF samples from virtual infants in the virtual population were randomly selected from any time point within the full dosing interval. Using this simulated practice data allowed for showing the parameter estimation of the GFR fraction parameter. Optimization using the simulated practice data yielded a GFR fraction of 0.35, which is close to the actual final model value of 0.30 when optimizing using the actual observed Prophylaxis Study data. Actual observed data for model development and evaluation could not be included in this repository posting as it is only accessible through a data use agreement.;
Model compliance with original publication: Yes;
Model implementation requiring submitter’s additional knowledge: No;
Modelling context description: Fluconazole is used to treat hematogenous Candida meningoencephalitis in preterm and term infants. To characterize plasma and central nervous system exposure, an adult fluconazole physiologically-based pharmacokinetic (PBPK) model was scaled to infants, accounting for age dependencies in glomerular filtration and metabolism. The model was optimized using 760 plasma samples from 166 infants (median postmenstrual age (range) 28 weeks (24-50)) and 27 cerebrospinal fluid (CSF) samples from 22 infants (postmenstrual age 28 weeks (24-33)). Simulations evaluated achievement of the surrogate efficacy target of area under the unbound concentration-time curve greater than or equal to 400 mg*hour/L over the dosing interval in plasma and CSF using dosing guidelines. Average fold error of predicted concentrations was 0.73 and 1.14 for plasma and CSF, respectively. Target attainment in plasma and CSF was reached faster after incorporating a loading dose of 25 mg/kg. PBPK modeling can be useful in exploring CNS kinetics of drugs in children.;
Modelling task in scope: simulation;
Nature of research: Clinical research & Therapeutic use;
Therapeutic/disease area: CNS; Anti-infectives;
Annotations are correct.
This model is not certified.
  • Model owner: Jacqueline Gerhart
  • Submitted: Oct 29, 2019 2:13:39 PM
  • Last Modified: Oct 29, 2019 2:13:39 PM
Revisions
  • Version: 12 public model Download this version
    • Submitted on: Oct 29, 2019 2:13:39 PM
    • Submitted by: Jacqueline Gerhart
    • With comment: Updated to add renamed output file.
 
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