Study of Dopamine Transporter Receptor Occupancy With Long-acting Dex-methylphenidate
Condition: Drug Binding to DAT Receptors
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      The objectives of this study are to document the pharmacokinetics of the adequacy of DAT
      receptor occupancy d-MPH formulation in three doses (20 mg, 30 mg, and 40 mg) using PET
      scanning with C-11 Altropane as the ligand across a range of times. It has been estimated
      that MPH is effective when the average CNS DAT occupancy is 50% or greater. Focalin XR has
      been shown to be clinically effective in an analog classroom as early as 1 hour and as late
      as 12 hours. Therefore, it is hypothesized that the average DAT occupancy will be adequate
      (50% or greater) at time periods corresponding to the times of clinical efficacy.

      The first objective is to examine the onset of action by testing whether average DAT
      occupancy will be adequate (50% or greater) at 1 hour after dosing for each dose tested (20
      mg, 30 mg, 40 mg).

      The second objective is to test the adequacy of average DAT occupancy in a range of later
      times for each dose. The times chosen (8, 10 and 12 hours) correspond to times Focalin XR has
      been shown to be clinically effective in an analogue classroom study. A range of times have
      been chosen since, while effective at 12 hours, the degree of clinical effectiveness
      decreased with later time periods. The adequacy of DAT occupancy across this range of time
      periods will provide important details on the in vivo molecular action of the medicine at
      periods of critical clinical activity.

      The third exploratory objective is to examine a time period later then those previously
      tested with the highest dose. Since the clinical effectiveness of Focalin XR has not been
      tested out to 14 hours, it is unknown whether it is effective at 14 hours. If Focalin XR were
      to be effective at 14 hours it would be more likely at the highest dose.
    

Detailed description: 
      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.
    

Intervention name(s): dex-methylphenidate
Intervention type(s): Drug
Intervention description(s): The drug is administered as a capsule by mouth. Participants are assigned to receive either 20, 30 or 40 mg doses before each scan visit.
Other intervention name(s): Focalin XR
Intervention MeSH terms: Methylphenidate; Dexmethylphenidate Hydrochloride
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: Focalin XR; Adult; PET scan