Safety and pharmacokinetics of antipsychotics in children with autism

Antipsychotics are the cornerstone in the treatment of behavioural problems in
children with autism spectrum disorder. Unfortunately, treatment with
anti-psychotics is associated with a number of serious side effects.
Extrapyramidal side effects are irreversible and have a very negative impact on
adherence. Metabolic abnormalities are of even greater concern because they
increase the risk of diabetes and cardiovascular problems considerably. In
adults there is evidence that dosing antipsychotic drugs according to
Therapeutic Drug Monitoring (TDM) may reduce side effects. TDM may be even more
important in children because they are experiencing rapid changes in their
development. However, there are no studies that have looked at the association
between antipsychotic plasma concentrations and both efficacy and side effects
in children.

Our main objective is to develop a pharmacokinetic safety window in children
and adolescents for the three most prescribed antipsychotics in the
Netherlands, risperidone, pipamperon and aripiprazole. To this end we will
study the relation of the measured pharmacokinetic parameters with weight
change and extrapyramidal side effects over a 6 month period using a minimally
invasive Dry Blood Spot technique (DBS).
As a secondary objective, we will investigate the relation between the plasma
levels of the antipsychotics and cardiac changes, metabolic abnormalities,
somnolence and clinical effectiveness.

We will conduct a multicentre, prospective, observational cohort study. No
study intervention will occur. We will include 50 patients in each treatment
group which will be followed for 6 months. In this period, extrapyramidal,
metabolic and cardiac parameters are monitored. At 2 moments, we will obtain a
plasma day curve of the antipsychotic agent with the Dried Blood Spot (DBS)
technique.

Monitoring of metabolic status by registration of physical parameters are
standard clinical practice in most treatment centres. In the Erasmus MC regular
lab check ups and monitoring of treatment efficacy by means of questionnaires
is standard clinical practice as well.
Compared to standard clinical care, the following examinations have been added:
1/ ECG before start and after 6 months of study for every child (instead of on
indication only). 2/ Plasma day curves of the agents under study, using the
minimally invasive DBS method, a finger prick procedure at 2 moments,
consisting of 2 finger pricks a day. 3/ Two extra venipunctures 4/ The Epworth
Sleepiness Scale which takes 2-3 minutes to complete and focuses on daytime
sleepiness. 5/ Observation scales that are completed by the treating physician
and only takes several minutes.
The risks are negligible and only include local irritation from the
fingerprick. As a benefit, the intensified and standardised follow-up might
facilitate early detection of side effects. Moreover, should the study succeed
in demonstrating a relationship between drug plasma levels and side effects,
side effects in this vulnerable group may be limited in the future in a
minimally invasive way.
The study cannot be performed in adults, due to development-specific aspects of
both the pharmacokinetic and pharmacodynamics processes.