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

Abstract

AimsAripiprazole 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.MethodsTwenty‐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.ResultsFor 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.ConclusionsOur 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.

Towards Precision Medicine in Clinical Practice: Alinity C vs. UHPLC-MS/MS in Plasma Aripiprazole Determination

“…In this regard, achieving optimal therapeutic outcomes of aripiprazole requires the precise monitoring of plasma concentrations. In this sense, accurate quantification of aripiprazole is crucial for tailoring treatment strategies to individual patient needs, minimizing adverse effects and optimizing therapeutic efficacy [ 11 , 12 ]. Liquid chromatographic methods for the analysis of aripiprazole are widely described in the literature: there are LC-MS/MS [ 13 , 14 , 15 , 16 ], HPLC-UV/DAD [ 17 , 18 , 19 ] or GC-MS [ 20 ]-based methods.…”