Stimulants have been shown to be very effective in the treatment of Attention Deficit Hyperactivity Disorder (ADHD). \[1\] Studies have shown that full day treatment is often preferable to shorter treatment \[2\] and recent guidelines advise full day treatment. \[3\] However, there are many barriers to giving multiple doses of short acting medicine. New delivery systems have evolved to overcome tachyphylaxis and provide effective long-acting treatment with a single pill. \[4\] One of the new formulations is the spheroidal oral drug absorption system (SODAS). SODAS consists of capsules with two types of beads in a 1 to 1 ratio. One type of bead provides immediate release methylphenidate (IR MPH), and the other type of bead consists of MPH coated with a polymer that delays release for 4 hours. SODAS MPH has been shown to be effective in clinical studies \[5\]. However, the mechanism of action remains unclear. While pharmacokinetic studies have shown a double pulse profile in the serum \[4\], the central nervous system pharmacokinetics are unknown. Understanding the central nervous system pharmacokinetic properties is critical for new drug development for ADHD, especially for drugs of different lengths of action.
The d-MPH form has been shown to be the active enantiomer of MPH. Studies have shown that the duration of action of d-MPH is longer than that of racemic MPH. Clinical studies of once a day d-MPH has demonstrated efficacy in children, adolescents and adults with ADHD. Understanding the central nervous system pharmacokinetic properties of the SODAS formulation of the longer-acting (d) enantiomer will provide critical knowledge of its mechanism of action.
The main target of MPH in the brain is the dopamine transporter (DAT) \[6\]. There is now an exquisitely sensitive methodology to measure DAT occupancy using C-11 Altropane and Positron Emission Tomography (PET) \[7\]. The time course of decay of the C-11 Altropane permits repeated imaging, thus allowing documentation of the pharmacokinetics of DAT receptor occupancy. A group at Massachusetts General Hospital has previously documented the central nervous system pharmacokinetics of several psychiatric drugs using similar techniques \[8-12\].
To this end, this protocol seeks to document the pharmacokinetics of DAT receptor occupancy of d-MPH using PET and C-11 Altropane. It has been estimated that MPH is effective when the CNS DAT occupancy is 50% or greater. This aim of this study will be to measure CNS DAT occupancies at extended time points after administration of d-MPH. This research will provide novel and unique information toward a better understanding of the mechanism of action of long-acting stimulant formulations to enable new drug development.
