Towards precision dosing of aripiprazole in children and adolescents with autism spectrum disorder: Linking blood levels to weight gain and effectiveness

Rebecca A. Hermans, Sebastiaan D.T. Sassen, Sanne Maartje Kloosterboer, Catrien G. Reichart, Mirjam E.J. Kouijzer, Matthias M.J. de Kroon, Dennis Bastiaansen, Daphne van Altena, Ron H.N. van Schaik, Kazem Nasserinejad, Manon H.J. Hillegers, Birgit C.P. Koch*, Bram Dierckx, Brenda C.M. de Winter

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Aripiprazole is one of the most commonly prescribed antipsychotic drugs to children and adolescents worldwide, but it is associated with serious side-effects, including weight gain. This study assessed the population pharmacokinetics of aripiprazole and its active metabolite and investigated the relationship between pharmacokinetic parameters and body mass index (BMI) in children and adolescents with autism spectrum disorder (ASD) and behavioural problems. Secondary outcomes were metabolic, endocrine, extrapyramidal and cardiac side-effects and drug effectiveness. 


Twenty-four children and adolescents (15 males, 9 females) aged 6–18 years were included in a 24-week prospective observational trial. Drug plasma concentrations, side-effects and drug effectiveness were measured at several time points during follow-up. Relevant pharmacokinetic covariates, including CYP2D6, CYP3A4, CYP3A5 and P-glycoprotein (ABCB1) genotypes, were determined. Nonlinear mixed-effects modelling (NONMEM®) was used for a population pharmacokinetic analysis with 92 aripiprazole and 91 dehydro-aripiprazole concentrations. Subsequently, model-based trough concentrations, maximum concentrations and 24-h area under the curves (AUCs) were analysed to predict outcomes using generalized and linear mixed-effects models. 


For both aripiprazole and dehydro-aripiprazole, one-compartment models best described the measured concentrations, with albumin and BMI as significant covariates. Of all the pharmacokinetic parameters, higher sum (aripiprazole plus dehydro-aripiprazole) trough concentrations best predicted higher BMI z-scores (P <.001) and higher Hb1Ac levels (P =.03) during follow-up. No significant association was found between sum concentrations and effectiveness. 


Our results indicate a threshold with regard to safety, which suggests that therapeutic drug monitoring of aripiprazole could potentially increase safety in children and adolescents with ASD and behavioural problems.

Original languageEnglish
Pages (from-to)3026-3036
Number of pages11
JournalBritish Journal of Clinical Pharmacology
Issue number10
Early online date24 May 2023
Publication statusPublished - Oct 2023

Bibliographical note

Funding Information:
S.K., B.D. and B.K. received grant research support from The Netherlands Organization for Health Research and Development (ZonMW). R.H. received grant research support from ZonMw and Stichting de Merel. Funding information

Publisher Copyright:
© 2023 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.


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