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External Evaluation of Risperidone Population Pharmacokinetic Models Using Opportunistic Pediatric Data.

Publication ,  Journal Article
Karatza, E; Ganguly, S; Hornik, CD; Muller, WJ; Al-Uzri, A; James, L; Balevic, SJ; Gonzalez, D
Published in: Front Pharmacol
2022

Risperidone is approved to treat schizophrenia in adolescents and autistic disorder and bipolar mania in children and adolescents. It is also used off-label in younger children for various psychiatric disorders. Several population pharmacokinetic models of risperidone and 9-OH-risperidone have been published. The objectives of this study were to assess whether opportunistically collected pediatric data can be used to evaluate risperidone population pharmacokinetic models externally and to identify a robust model for precision dosing in children. A total of 103 concentrations of risperidone and 112 concentrations of 9-OH-risperidone, collected from 62 pediatric patients (0.16-16.8 years of age), were used in the present study. The predictive performance of five published population pharmacokinetic models (four joint parent-metabolite models and one parent only) was assessed for accuracy and precision of the predictions using statistical criteria, goodness of fit plots, prediction-corrected visual predictive checks (pcVPCs), and normalized prediction distribution errors (NPDEs). The tested models produced similarly precise predictions (Root Mean Square Error [RMSE]) ranging from 0.021 to 0.027 nmol/ml for risperidone and 0.053-0.065 nmol/ml for 9-OH-risperidone). However, one of the models (a one-compartment mixture model with clearance estimated for three subpopulations) developed with a rich dataset presented fewer biases (Mean Percent Error [MPE, %] of 1.0% vs. 101.4, 146.9, 260.4, and 292.4%) for risperidone. In contrast, a model developed with fewer data and a more similar population to the one used for the external evaluation presented fewer biases for 9-OH-risperidone (MPE: 17% vs. 69.9, 47.8, and 82.9%). None of the models evaluated seemed to be generalizable to the population used in this analysis. All the models had a modest predictive performance, potentially suggesting that sources of inter-individual variability were not entirely captured and that opportunistic data from a highly heterogeneous population are likely not the most appropriate data to evaluate risperidone models externally.

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Published In

Front Pharmacol

DOI

ISSN

1663-9812

Publication Date

2022

Volume

13

Start / End Page

817276

Location

Switzerland

Related Subject Headings

  • 3214 Pharmacology and pharmaceutical sciences
  • 1115 Pharmacology and Pharmaceutical Sciences
 

Citation

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Karatza, E., Ganguly, S., Hornik, C. D., Muller, W. J., Al-Uzri, A., James, L., … Gonzalez, D. (2022). External Evaluation of Risperidone Population Pharmacokinetic Models Using Opportunistic Pediatric Data. Front Pharmacol, 13, 817276. https://doi.org/10.3389/fphar.2022.817276
Karatza, Eleni, Samit Ganguly, Chi D. Hornik, William J. Muller, Amira Al-Uzri, Laura James, Stephen J. Balevic, and Daniel Gonzalez. “External Evaluation of Risperidone Population Pharmacokinetic Models Using Opportunistic Pediatric Data.Front Pharmacol 13 (2022): 817276. https://doi.org/10.3389/fphar.2022.817276.
Karatza E, Ganguly S, Hornik CD, Muller WJ, Al-Uzri A, James L, et al. External Evaluation of Risperidone Population Pharmacokinetic Models Using Opportunistic Pediatric Data. Front Pharmacol. 2022;13:817276.
Karatza, Eleni, et al. “External Evaluation of Risperidone Population Pharmacokinetic Models Using Opportunistic Pediatric Data.Front Pharmacol, vol. 13, 2022, p. 817276. Pubmed, doi:10.3389/fphar.2022.817276.
Karatza E, Ganguly S, Hornik CD, Muller WJ, Al-Uzri A, James L, Balevic SJ, Gonzalez D. External Evaluation of Risperidone Population Pharmacokinetic Models Using Opportunistic Pediatric Data. Front Pharmacol. 2022;13:817276.

Published In

Front Pharmacol

DOI

ISSN

1663-9812

Publication Date

2022

Volume

13

Start / End Page

817276

Location

Switzerland

Related Subject Headings

  • 3214 Pharmacology and pharmaceutical sciences
  • 1115 Pharmacology and Pharmaceutical Sciences