SPACe 2 STAR : Safety and pharmacokinetics of antipsychotics in children 2. Studying TDM in An RCT

An autism spectrum disorder (ASD) is characterised by impairments in social
interaction, verbal and nonverbal communication, as well as by stereotypical
patterns of behaviour and interests (American Psychiatric Association, 2013).
Apart from these core symptoms, children and adolescents with ASD frequently
display behaviour such as temper tantrums, aggression and self-harm
(Lecavalier, 2006). Indeed, a Dutch study showed that almost half of the
children and adolescents diagnosed with ASD suffered from a comorbid
behavioural disorder as well (de Bruin, Ferdinand, Meester, de Nijs, & Verheij,
2007). Pharmacological interventions are an important part of the multimodal
treatment of the comorbid behavioural problems. National and international
guidelines recommend antipsychotics as agents of first choice (Werkgroep
richtlijn autisme en aanverwante stoornissen bij kinderen en jeugdigen van de
Nederlandse Vereniging voor Psychiatrie, 2009). Our research has shown that
antipsychotic use in the Netherlands is high, with almost 10 out of every 1000
children and adolescents using antipsychotic medication (Kloosterboer, et al.,
2018). Previously, few studies have adequately monitored long term
antipsychotic safety profiles, though evidence indicates that extrapyramidal
symptoms, cardiovascular and especially metabolic abnormalities are clinically
relevant adverse effects in younger patients, with the individual agents
differing in their propensity to induce side effects (Caccia, 2013; Cohen,
Bonnot, Bodeau, Consoli, & Laurent, 2012). In atypical antipsychotics, the most
prescribed class of antipsychotics in children and adolescents, metabolic
abnormalities are of greater concern (Cohen, et al., 2012). In short term
studies in children, weight gain amounted to an approximately 10% increase when
compared to baseline (Aman, et al., 2002). In addition, antipsychotics have
been reported to increase triglycerides by up to 45% (Meyer & Koro, 2004).
Recently a large-scale epidemiological study showed that children receiving
antipsychotic medication had a 3-fold increased risk of developing type 2
diabetes when compared to healthy controls (Bobo, et al., 2013). Moreover,
childhood obesity is highly predictive of adulthood obesity (Ogden, 2007) and
when childhood obesity persists in adulthood, these adults are at an even
higher risk of type 2 diabetes, hypertension, dyslipidemia, and atherosclerosis
compared to persons with adult-onset obesity (Juonala, 2011). In adults there
is evidence that therapeutic drug monitoring (TDM), i.e. the quantification of
serum drug concentrations for dose optimization, can help in maximizing
clinical efficacy while minimizing the risk of side effects (Hiemke, et al.,
2011). Several studies have shown a relationship between risperidone and
aripiprazole plasma levels and both clinical efficacy and extrapyramidal side
effects (Mauri et al. 2007; Kirschbaum et al. 2008). Previously however, no
study had targeted the relation between drug plasma levels and indices of
metabolic side effects in adults. In children and adolescents, only a few
studies have been performed investigating the relationship between risperidone
and aripiprazole, and response or side-effects. However, all of these studies
have suboptimal study designs, as risperidone sampling was not performed under
standardized protocols or a retrospective design was Children are a unique
patient population because they not only differ physiologically and
anatomically from adults, but also experience rapid changes in growth and
development in the course of their childhood. That is why in the ZonMW GGG
funded (2015) SPACe study we researched the relationship between drug plasma
levels and metabolic side effects in children. To this end we first developed
an analytic method that allowed us to quantify drug plasma levels using a dry
blood spot method (DBS), where blood is obtained by means of a finger prick,
and dried on a filter paper. This minimally invasive procedure, is well
tolerated by children with ASD (Kloosterboer, et al., 2020). We successfully
validated this method for the simultaneous quantification of risperidone and
its metabolite 9-OH risperidone, and aripiprazole and its metabolite
dehydroaripiprazole (Tron, 2017, Kloosterboer 2018). In 42 children who used
risperidone and 23 children who used aripiprazole we developed population
pharmacokinetic models. We used these models to show a clear relationship of
risperidone and aripiprazole trough concentrations with weight gain over a 6
month period (Kloosterboer, 2020; Hermans, 2022 manuscript). From the data
collected in SPACe 1, we defined optimal therapeutic plasma level windows for
risperidone and aripiprazole. For risperidone, this window is between 3.5 and 7
µg/L with 5.25 µg/L as an optimal aim, as dosing towards the middle of the
window will give the best chance of neither dosing over nor under the cut-off
values. We found that at risperidone plasma levels above 7 µg/L one month after
start of treatment, 87.5% of children had significant weight gain compared to
35% below this cut-off. 75% of children with a risperidone plasma level above
3.5 µg/L experienced significant therapeutic effect as measured with the
Aberrant Behavior Checklist, while this was only the case for 36% of children
with plasma levels below this cut-off. Based on retrospective data analysis, we
found a therapeutic window for aripiprazole between 50 and 20 µg/L with 35 µg/L
as an optimal aim. Plasma levels of aripiprazole above 50 µg/L showed
significant weight gain after 1 year.

This study has been transitioned to CTIS with ID 2024-511568-96-00 check the CTIS register for the current data.

In SPACe 2 STAR, we aim to reach further, we will test whether application of
TDM in clinical practice is indeed able to reduce the number/severity of
metabolic side effects, while retaining clinical effectiveness in children by
means of a randomized controlled trial.

We will study the ability of TDM to reduce risperidone and aripiprazole induced
side effects in a randomized control trial. Patients will be randomized to
receive therapeutic drug monitoring or to care as usual (CAU), which does not
include therapeutic drug monitoring. In the TDM arm, trough drug plasma levels
will be measured by means of DBS at 4 and 10 weeks in steady state after start
of antipsychotics treatment. Based on these plasma levels dosing advice will be
given to the treating physicians. In the CAU arm plasma levels will be
determined and no dosing recommendations given. Metabolic parameters (BMI,
cholesterol, triglycerides) as well irritability/aggression symptom severity
will be measured in both arms at baseline (before start of antipsychotic
treatment), and 4, 10, 24 and 52 weeks later. With a follow-up time of one
year, we will be able to determine the value of our intervention over a longer
time period.

Therapeutic drug monitoring (TDM) versus care as usual for children receiving
risperidon or aripiprazole treatment.

All of the participants will be subjected to two additional fingerpricks. In
addition they and/or their parents/caregivers will be asked to complete
multiple questionnaires at five time points. The total extra time investment is
estimated at 2,5 hours.The control group receive traditional care as usual.

Prescription of risperidone and aripiprazole is in accordance with national and
international guidelines. Dosages will not exceed recommended dosages in these
guidelines. There is extensive experience with risperidone and aripiprazole in
routine clinical practice, we therefore do not expect many or new SUSARs.
During the course of the treatment, we will monitor participants for changes in
their health status which warrant dose reduction or termination of study
treatment.

In the group receiving therapeutic drug monitoring and dosing advice children
may receive a lower dose of the medicine than he / she would otherwise have
received. This may lead to a delayed or lessened effect of risperidone and
aripiprazole