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

• Published in: British journal of clinical pharmacology 2023-10, Vol.89 (10), p.3026-3036
• Main Authors: Hermans, Rebecca A, Sassen, Sebastiaan D T, Kloosterboer, Sanne Maartje, Reichart, Catrien G, Kouijzer, Mirjam E J, de Kroon, Matthias M J, Bastiaansen, Dennis, van Altena, Daphne, van Schaik, Ron H N, Nasserinejad, Kazem, Hillegers, Manon H J, Koch, Birgit C P, Dierckx, Bram, de Winter, Brenda C M
• Format: Article
• Language: English
• ISSN: 0306-5251; 1365-2125; 1365-2125
• DOI: 10.1111/bcp.15800

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