Towards precision dosing of aripiprazole in children and adolescents with autism spectrum disorder: Linking blood levels to weight gain and effectiveness.
antipsychotics
paediatric patients
pharmacometrics
precision dosing
side-effects
Journal
British journal of clinical pharmacology
ISSN: 1365-2125
Titre abrégé: Br J Clin Pharmacol
Pays: England
ID NLM: 7503323
Informations de publication
Date de publication:
10 2023
10 2023
Historique:
revised:
07
04
2023
received:
06
12
2022
accepted:
04
05
2023
medline:
15
9
2023
pubmed:
24
5
2023
entrez:
24
5
2023
Statut:
ppublish
Résumé
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.
Substances chimiques
Aripiprazole
82VFR53I78
Antipsychotic Agents
0
Types de publication
Observational Study
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3026-3036Informations de 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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