Pharmacokinetics in Plasma and Saliva of a Single Dose Immediate- or Extended-Release Methylphenidate in Healthy Volunteers.

Despite frequent use of methylphenidate in children with attention
deficit/hyperactivity disorder (ADHD), very little is known about its
metabolism or the relationship between the time-course of effects related to
blood levels. Recently, a study was performed in children with ADHD in which
acute effects of one dose immediate-release (IR) methylphenidate (MPH) were
measured non-invasively using the Neurocart. As blood sampling is undesirable
in children in the setting of a non-therapeutic study, saliva samples were
collected to measure MPH concentration. By combining these data with
pharmacokinetic data in blood, a PK model can be build that provides us with
estimated plasma drug levels in children needed for population PK/PD analysis.
However, only limited data have been published on the PK of MPH in serum and/or
saliva, and if published, data were pooled. Therefore, a study in healthy
volunteers is needed in which both plasma and saliva samples will be obtained
prior and post administration of medication.
The aim of the proposed study is to elucidate pharmacokinetic plasma and saliva
profiles of 10 mg MPH-IR, and to describe the relationship between plasma and
saliva concentrations (for use in the analysis of data in the previous study).
In addition, the possible effect of saliva pH (and saliva flow) on MPH saliva
concentration will be investigated as previous studies on drugs in saliva have
shown that other weak bases tend to concentrate in saliva. As another planned
study involves investigation of medication levels and observed acute effects of
MPH in an osmotic controlled-release oral delivery system (OROS) in ADHD
children, these steps will also be performed for 18 mg MPH-OROS. In addition,
blood samples will be collected for future study in more subjects on potential
gene polymorphism affecting MPH PK. With exception of one recent small study by
Nemoda and colleagues (2009), genetic analyses of drug metabolizing enzymes
have not been carried out in relation to MPH. Human liver carboxylesterase 1A1
(hCE1A1) might be a good candidate for genetic analysis in our study, as it is
responsible for the hydrolysis of both the D- and L-isomer of MPH, and for the
resulting first-pass, stereoselective metabolism of the drug (Sun et al.
469-76). Expression and activity of hCE1 is age-related and CES enzymes are
regulated by nuclear receptor enzymes. It is (yet) unknown which nuclear
receptor enzymes are responsible for the regulation of hCE1.

To establish the pharmacokinetic profiles of saliva and plasma concentration of
10 mg MPH-IR and 18 mg MPH-OROS in healthy volunteers; to investigate whether
there is a correlation between saliva- and plasma levels of MPH-IR and
MPH-OROS, and if present, to describe this relationship; to determine the
effect of saliva pH on MPH saliva concentration; to explore the potential
influence of a hCE1A1 (human carboxylesterase 1A1) polymorphism on the plasma
concentration time profile of MPH. If indicated, polymorphisms of regulator
enzymes, like nuclear receptor enzymes, will also be explored in the future.

Randomized open label cross-over study.

10 mg MPH-IR or 18 mg MPH-OROS.

Negligible burden and minimal risk.