A recent study exploring the relationship between aripiprazole pharmacokinetics (PK), side effects, and effectiveness in children and adolescents with autism spectrum disorder (ASD) has found that higher plasma levels correlate with greater weight gain.
This finding points to a threshold when it comes to safety and suggests that therapeutic drug monitoring of aripiprazole may help improve safety in this paediatric population with ASD and behavioural problems, according to the researchers.
“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,” they said.
This 24-week prospective observational trial included 24 children and adolescents (aged 6‒18 years, 15 males), whose drug plasma concentration, side effects, and drug effectiveness were measured at several time points during follow-up. Relevant PK covariates, such as CYP2D6, CYP3A4, CYP3A5, and P-glycoprotein (ABCB1) genotypes, were identified.
The researchers performed a population PK analysis with 92 aripiprazole and 91 dehydro-aripiprazole concentrations using nonlinear mixed-effects modeling. They then analysed the model-based trough concentrations, maximum concentrations, and 24-h area under the curves (AUCs) to predict outcomes using generalized and linear mixed-effects models.
One-compartment models appeared to be best when characterizing the measured concentrations for both aripiprazole and dehydro-aripiprazole, with albumin and body mass index (BMI) serving as significant covariates. [Br J Clin Pharmacol 2023;89:3026-3036]
During follow-up, higher sum (aripiprazole plus dehydro-aripiprazole) trough concentrations showed the strongest association with higher BMI z scores (p<0.001) and higher Hb1Ac levels (p=0.03) out of all the PK parameters assessed. Of note, no significant relationship was seen between sum concentrations and effectiveness.
Cutoff value
“Our findings lead to a considerably lower upper cutoff value than in the only previously proposed therapeutic window for aripiprazole in the paediatric population,” the researchers said. [J Neural Transm (Vienna) 2020;127:1663-1674]
“This therapeutic window for children and adolescents with all psychiatric diagnoses was proposed at aripiprazole plasma levels of 60.7–372.1 μg/L to have an improvement in CGI (effect),” they added.
Since the results of the current study were based on sum levels of aripiprazole and dehydro-aripiprazole rather than on aripiprazole levels alone, the difference in suggested limits was apparently higher. However, the researchers saw higher cutoff values (105–375.3 μg/L) only when considering patients with psychotic disorders, indicating different therapeutic reference ranges for different treatment indications.
“This finding only confirms the need for precision dosing using pharmacometrics which are targeted to specific populations,” they said.
“The correlation we found between higher plasma levels and a higher amount of weight gain suggests that there is a role for therapeutic drug monitoring in optimizing care and warrants further research,” according to the researchers.
“The clinical benefit of therapeutic drug monitoring of aripiprazole in this population will be investigated in a follow-up randomized controlled trial,” they added.