Risperidone plasma concentrations are associated with side effects and effectiveness in children and adolescents with autism spectrum disorder
British Journal of Clinical Pharmacology, vol. 87, pp. 1069–1081
Abstract
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.
Authors 17
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Sanne Maartje Kloosterboer corresponding
Erasmus MC · Erasmus MC - Sophia Children’s Hospital
Affiliation as printed
Department of Child and Adolescent Psychiatry/Psychology, Erasmus MC‐ Sophia Children's Hospital University Medical Center Rotterdam the Netherlands
Department of Hospital Pharmacy, Erasmus MC University Medical Center Rotterdam The Netherlands
Department of Child and Adolescent Psychiatry/Psychology, Erasmus MC- Sophia Children's Hospital, University Medical Center Rotterdam, the Netherlands
Department of Hospital Pharmacy, Erasmus MC, University Medical Center Rotterdam, The Netherlands
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Affiliation as printed
Department of Hospital Pharmacy, Erasmus MC University Medical Center Rotterdam The Netherlands
Department of Hospital Pharmacy, Erasmus MC, University Medical Center Rotterdam, The Netherlands
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Leiden University Medical Center
Affiliation as printed
Curium‐LUMC Child and Adolescent Psychiatry Leiden University Medical Center Oegstgeest The Netherlands
Curium-LUMC Child and Adolescent Psychiatry, Leiden University Medical Center, Oegstgeest, The Netherlands
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Affiliation as printed
GGz Breburg, Centre of Youth Breda the Netherlands
GGz Breburg, Centre of Youth, Breda, the Netherlands
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Affiliation as printed
de Kroon Child Psychiatry Breda the Netherlands
de Kroon Child Psychiatry, Breda, the Netherlands
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Affiliation as printed
Yulius Mental Health Dordrecht The Netherlands
Yulius Mental Health, Dordrecht, The Netherlands
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Leiden University Medical Center · Parnassia Groep
Affiliation as printed
Curium‐LUMC Child and Adolescent Psychiatry Leiden University Medical Center Oegstgeest The Netherlands
Parnassia Psychiatric Institute The Hague The Netherlands
Sarr Expert Centre for Autism Youz Child and Adolescent Psychiatry Rotterdam The Netherlands
Curium-LUMC Child and Adolescent Psychiatry, Leiden University Medical Center, Oegstgeest, The Netherlands
Parnassia Psychiatric Institute, The Hague, The Netherlands
Sarr Expert Centre for Autism, Youz Child and Adolescent Psychiatry, Rotterdam, The Netherlands
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Affiliation as printed
GGZ Delfland, Department of Youth Delft The Netherlands
GGZ Delfland, Department of Youth, Delft, The Netherlands
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Erasmus MC · Erasmus MC - Sophia Children’s Hospital
Affiliation as printed
Department of Child and Adolescent Psychiatry/Psychology, Erasmus MC‐ Sophia Children's Hospital University Medical Center Rotterdam the Netherlands
Department of Child and Adolescent Psychiatry/Psychology, Erasmus MC- Sophia Children's Hospital, University Medical Center Rotterdam, the Netherlands
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Erasmus MC · Erasmus MC - Sophia Children’s Hospital
Affiliation as printed
Department of Child and Adolescent Psychiatry/Psychology, Erasmus MC‐ Sophia Children's Hospital University Medical Center Rotterdam the Netherlands
Department of Child and Adolescent Psychiatry/Psychology, Erasmus MC- Sophia Children's Hospital, University Medical Center Rotterdam, the Netherlands
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Erasmus MC · Erasmus MC - Sophia Children’s Hospital
Affiliation as printed
Department of Pediatrics, Erasmus MC ‐ Sophia Children's Hospital University Medical Center Rotterdam the Netherlands
Department of Pediatrics, Erasmus MC - Sophia Children's Hospital, University Medical Center Rotterdam, the Netherlands
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Affiliation as printed
Department of Clinical Chemistry, Erasmus MC University Medical Center Rotterdam The Netherlands
Department of Clinical Chemistry, Erasmus MC, University Medical Center Rotterdam, The Netherlands
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Affiliation as printed
Department of Hematology, Erasmus MC University Medical Center Rotterdam The Netherlands
Department of Hematology, Erasmus MC, University Medical Center Rotterdam, The Netherlands
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Erasmus MC · Erasmus MC - Sophia Children’s Hospital
Affiliation as printed
Department of Child and Adolescent Psychiatry/Psychology, Erasmus MC‐ Sophia Children's Hospital University Medical Center Rotterdam the Netherlands
Department of Child and Adolescent Psychiatry/Psychology, Erasmus MC- Sophia Children's Hospital, University Medical Center Rotterdam, the Netherlands
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Affiliation as printed
Department of Hospital Pharmacy, Erasmus MC University Medical Center Rotterdam The Netherlands
Department of Hospital Pharmacy, Erasmus MC, University Medical Center Rotterdam, The Netherlands
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Erasmus MC · Erasmus MC - Sophia Children’s Hospital
Affiliation as printed
Department of Child and Adolescent Psychiatry/Psychology, Erasmus MC‐ Sophia Children's Hospital University Medical Center Rotterdam the Netherlands
Department of Child and Adolescent Psychiatry/Psychology, Erasmus MC- Sophia Children's Hospital, University Medical Center Rotterdam, the Netherlands
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Affiliation as printed
Department of Hospital Pharmacy, Erasmus MC University Medical Center Rotterdam The Netherlands
Department of Hospital Pharmacy, Erasmus MC, University Medical Center Rotterdam, The Netherlands
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