Saliva pharmacokinetics of methylphenidate (MPH) following ingestion of immediate and sustained release formulations in children with attention- deficit hyperactivity disorder (ADHD)

Rationale: Attention- deficit hyperactivity disorder (ADHD) is one of the most
frequently encountered psychiatric disorders in the pediatric out clinic. In
the Netherlands the incidence of ADHD is 5% and half of the patients have
received or receive pharmacotherapy1,2. The drug of first choice is
methylphenidate (MPH). Little is known about the pharmacokinetics and
pharmacodynamics of MPH in children due to medical-ethical issues when
performing pediatric clinical trials. MPH is metabolized by esterases that can
be measured in DNA from saliva. Slow, normal ad extensive metabolisers exist
which can discriminated on basis of their genotype.
MPH therapy is routineously initiated with an immediate release formulation.
Subsequently, children are switched to a dose-equivalent formulation with
sustained release. MPH sustained release formulations are preferred above
immediate release preparations since they have to be taken less frequently,
which favors drug adherence. In clinical practice however, the switch of
formulations results in less efficacy in some patients while other patient
experience more adverse effects. This difference may be due to differences in
bioavailability of the formulations or to fluctuating plasma levels during the
day.
In a recent study differences have been observed in the time profiles of
hormonal concentrations in saliva (cortisol, testosterone,
dehydroepiandrosteron (DHEA)) in children with ADHD when compared to healthy
controls3,4,5. These differences may be important with respect to behavior and
the development of children with ADHD, which is delayed compared to healthy
controls.

Objective: Main objective of this study is to compare the area under the MPH
saliva concentration versus time curve (AUC) following ingestion of immediate
and sustained release formulations of MPH in children with ADHD. Secondary
objectives are: 1. The comparison of time profiles of the hormones cortisol,
testosterone and DHEA for the different formulations The profiles will be
compared to the profiles of the children before starting medication. 2:
Evaluation of the relationship between the esterase genotype and MPH clearance
and elimination halflife.

The study is designed as an observational study. Children diagnosed with ADHD
(6 to 18 year) who are visiting the paediatric outpatient clinic of the
Maasstadziekenhuis will be asked to participate. Participating patients will
receive MPH therapy according to clinical routine. Therapy is started with an
immediate release formulation of MPH and the MPH dose is individually titrated.
After optimal titration with no undesirable side effects the patient is
routinely advised to switch to a sustained release formulation.

Separate saliva concentration versus time profile of MPH and the hormones will
be assessed for both the immediate release and sustained formulation. Each
patient will serve as its own control.

The saliva pharmacokinetics of MPH will be investigated for 4 sustained release
formulations (Concerta®, Equasym XL® , Medikinet CR® of methylfenidaat
Retard-Regenboogapotheek), which are all registered for the treatment of ADHD.
In each child the pharmacokinetics of only one sustained release form will be
studied. For each formulation 10 children will be included, so a total of 40
children will be included for the whole study.

The time profiles of the hormones cortisol, testosterone and DHEA in saliva
will be assessed before the start of MPH therapy and for both the immediate
release and sustained formulation. A partictipating patient will provide 3
saliva curves: pretreatment, immediate release and sustained release.

no risks are involved, the study burden is low