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Risperidone plasma concentrations are associated with side effects and effectiveness in children and adolescents with autism spectrum disorder

AIM: Risperidone is the most commonly prescribed antipsychotic drug to children and adolescents worldwide, but it is associated with serious side effects, including weight gain. This study assessed the relationship of risperidone and 9‐hydroxyrisperidone trough concentrations, maximum concentrations...

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Autores principales: Kloosterboer, Sanne Maartje, de Winter, Brenda C.M., Reichart, Catrien G., Kouijzer, Mirjam E.J., de Kroon, Matthias M.J., van Daalen, Emma, Ester, Wietske A., Rieken, Rob, Dieleman, Gwen C., van Altena, Daphne, Bartelds, Beatrijs, van Schaik, Ron H.N., Nasserinejad, Kazem, Hillegers, Manon H.J., van Gelder, Teun, Dierckx, Bram, Koch, Birgit C.P.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9328651/
https://www.ncbi.nlm.nih.gov/pubmed/32643213
http://dx.doi.org/10.1111/bcp.14465
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author Kloosterboer, Sanne Maartje
de Winter, Brenda C.M.
Reichart, Catrien G.
Kouijzer, Mirjam E.J.
de Kroon, Matthias M.J.
van Daalen, Emma
Ester, Wietske A.
Rieken, Rob
Dieleman, Gwen C.
van Altena, Daphne
Bartelds, Beatrijs
van Schaik, Ron H.N.
Nasserinejad, Kazem
Hillegers, Manon H.J.
van Gelder, Teun
Dierckx, Bram
Koch, Birgit C.P.
author_facet Kloosterboer, Sanne Maartje
de Winter, Brenda C.M.
Reichart, Catrien G.
Kouijzer, Mirjam E.J.
de Kroon, Matthias M.J.
van Daalen, Emma
Ester, Wietske A.
Rieken, Rob
Dieleman, Gwen C.
van Altena, Daphne
Bartelds, Beatrijs
van Schaik, Ron H.N.
Nasserinejad, Kazem
Hillegers, Manon H.J.
van Gelder, Teun
Dierckx, Bram
Koch, Birgit C.P.
author_sort Kloosterboer, Sanne Maartje
collection PubMed
description AIM: Risperidone is the most commonly prescribed antipsychotic drug to children and adolescents worldwide, but it is associated with serious side effects, including weight gain. This study assessed the relationship of risperidone and 9‐hydroxyrisperidone trough concentrations, maximum concentrations and 24‐hour area under the curves (AUCs) with body mass index (BMI) z‐scores in children and adolescents with autism spectrum disorder (ASD) and behavioural problems. Secondary outcomes were metabolic, endocrine, extrapyramidal and cardiac side effects and effectiveness. METHODS: Forty‐two children and adolescents (32 males) aged 6‐18 years were included in a 24‐week prospective observational trial. Drug plasma concentrations, side effects and effectiveness were measured at several time points during follow‐up. Relevant pharmacokinetic covariates, including medication adherence and CYP2D6, CYP3A4, CYP3A5 and P‐glycoprotein (ABCB1) genotypes, were measured. Nonlinear mixed‐effects modelling (NONMEM®) was used for a population pharmacokinetic analysis with 205 risperidone and 205 9‐hydroxyrisperidone concentrations. Subsequently, model‐based trough concentrations, maximum concentrations and 24‐hour AUCs were analysed to predict outcomes using generalized and linear mixed‐effects models. RESULTS: A risperidone two‐compartment model combined with a 9‐hydroxyrisperidone one‐compartment model best described the measured concentrations. Of all the pharmacokinetic parameters, higher risperidone sum trough concentrations best predicted higher BMI z‐scores during follow‐up (P < .001). Higher sum trough concentrations also predicted more sedation (P < .05), higher prolactin levels (P < .001) and more effectiveness measured with Aberrant Behavior Checklist irritability score (P < .01). CONCLUSION: Our results indicate a therapeutic window exists, which suggests that therapeutic drug monitoring of risperidone might increase safety and effectiveness in children and adolescents with ASD and behavioural problems.
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spelling pubmed-93286512022-07-30 Risperidone plasma concentrations are associated with side effects and effectiveness in children and adolescents with autism spectrum disorder Kloosterboer, Sanne Maartje de Winter, Brenda C.M. Reichart, Catrien G. Kouijzer, Mirjam E.J. de Kroon, Matthias M.J. van Daalen, Emma Ester, Wietske A. Rieken, Rob Dieleman, Gwen C. van Altena, Daphne Bartelds, Beatrijs van Schaik, Ron H.N. Nasserinejad, Kazem Hillegers, Manon H.J. van Gelder, Teun Dierckx, Bram Koch, Birgit C.P. Br J Clin Pharmacol Original Articles AIM: Risperidone is the most commonly prescribed antipsychotic drug to children and adolescents worldwide, but it is associated with serious side effects, including weight gain. This study assessed the relationship of risperidone and 9‐hydroxyrisperidone trough concentrations, maximum concentrations and 24‐hour area under the curves (AUCs) with body mass index (BMI) z‐scores in children and adolescents with autism spectrum disorder (ASD) and behavioural problems. Secondary outcomes were metabolic, endocrine, extrapyramidal and cardiac side effects and effectiveness. METHODS: Forty‐two children and adolescents (32 males) aged 6‐18 years were included in a 24‐week prospective observational trial. Drug plasma concentrations, side effects and effectiveness were measured at several time points during follow‐up. Relevant pharmacokinetic covariates, including medication adherence and CYP2D6, CYP3A4, CYP3A5 and P‐glycoprotein (ABCB1) genotypes, were measured. Nonlinear mixed‐effects modelling (NONMEM®) was used for a population pharmacokinetic analysis with 205 risperidone and 205 9‐hydroxyrisperidone concentrations. Subsequently, model‐based trough concentrations, maximum concentrations and 24‐hour AUCs were analysed to predict outcomes using generalized and linear mixed‐effects models. RESULTS: A risperidone two‐compartment model combined with a 9‐hydroxyrisperidone one‐compartment model best described the measured concentrations. Of all the pharmacokinetic parameters, higher risperidone sum trough concentrations best predicted higher BMI z‐scores during follow‐up (P < .001). Higher sum trough concentrations also predicted more sedation (P < .05), higher prolactin levels (P < .001) and more effectiveness measured with Aberrant Behavior Checklist irritability score (P < .01). CONCLUSION: Our results indicate a therapeutic window exists, which suggests that therapeutic drug monitoring of risperidone might increase safety and effectiveness in children and adolescents with ASD and behavioural problems. John Wiley and Sons Inc. 2020-07-26 2021-03 /pmc/articles/PMC9328651/ /pubmed/32643213 http://dx.doi.org/10.1111/bcp.14465 Text en © 2020 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
spellingShingle Original Articles
Kloosterboer, Sanne Maartje
de Winter, Brenda C.M.
Reichart, Catrien G.
Kouijzer, Mirjam E.J.
de Kroon, Matthias M.J.
van Daalen, Emma
Ester, Wietske A.
Rieken, Rob
Dieleman, Gwen C.
van Altena, Daphne
Bartelds, Beatrijs
van Schaik, Ron H.N.
Nasserinejad, Kazem
Hillegers, Manon H.J.
van Gelder, Teun
Dierckx, Bram
Koch, Birgit C.P.
Risperidone plasma concentrations are associated with side effects and effectiveness in children and adolescents with autism spectrum disorder
title Risperidone plasma concentrations are associated with side effects and effectiveness in children and adolescents with autism spectrum disorder
title_full Risperidone plasma concentrations are associated with side effects and effectiveness in children and adolescents with autism spectrum disorder
title_fullStr Risperidone plasma concentrations are associated with side effects and effectiveness in children and adolescents with autism spectrum disorder
title_full_unstemmed Risperidone plasma concentrations are associated with side effects and effectiveness in children and adolescents with autism spectrum disorder
title_short Risperidone plasma concentrations are associated with side effects and effectiveness in children and adolescents with autism spectrum disorder
title_sort risperidone plasma concentrations are associated with side effects and effectiveness in children and adolescents with autism spectrum disorder
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9328651/
https://www.ncbi.nlm.nih.gov/pubmed/32643213
http://dx.doi.org/10.1111/bcp.14465
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