title: Understanding the central pharmacokinetics of spheroidal oral drug absorption system (SODAS) dexmethylphenidate: a positron emission tomography study of dopamine transporter receptor occupancy measured with C-11 altropane.
abstract: OBJECTIVE
  Pediatric studies of the long-acting formulation (spheroidal oral drug absorption system [SODAS]) of the isomer dexmethylphenidate have shown a dose-dependent efficacy through 12 hours. However, there are no studies of central nervous system (CNS) dopamine transporter occupancies.
  
  
  METHODS
  Eighteen healthy volunteers underwent positron emission tomography (PET) imaging with C-11 altropane before and after administration of oral doses of SODAS dexmethylphenidate. Each group of 6 subjects received 1 of 3 doses (20 mg, 30 mg, 40 mg) before PET imaging at 1, 8, 10, 12 (20 mg and 30 mg), or 1, 8, 10, and 14 (40 mg) hours after dosing. Transporter occupancy was calculated by standard methods. The study was conducted from January 2007 through December 2007.
  
  
  RESULTS
  For all doses, plasma dexmethylphenidate levels and CNS dopamine transporter occupancies were greatest at 8 hours and decreased over time at 10, 12, and 14 hours. Plasma dexmethylphenidate levels were correlated to dose (P < .003). Mean plasma levels were ≥ 6 ng/mL to at least 8 hours with 20 mg (5.7 ng/mL), 10 hours with 30 mg, and 12 hours (extrapolated) with 40 mg. Dopamine transporter occupancies in the right caudate were 47% at 8 hours with 20 mg, 42% at hour 10 with 30 mg, and 46% (extrapolated) at hour 12 with 40 mg. Dopamine transporter occupancy was significantly correlated with plasma concentration of dexmethylphenidate (P < .001).
  
  
  CONCLUSIONS
  These results confirm the study hypothesis that central dopamine transporter occupancy parallels peripheral pharmacokinetic findings in orally administered long-acting dexmethylphenidate in later hours after administration.
  
  
  BACKGROUND
  clinicaltrials.gov Identifier: NCT00593138.
authors.affiliation: The Pediatric Psychopharmacology Unit, Massachusetts General Hospital, Boston, MA 02114, USA. tspencer@partners.org
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Spencer
authors.forename: Ali A
authors.initials: AA
authors.lastname: Bonab
authors.forename: Darin D
authors.initials: DD
authors.lastname: Dougherty
authors.forename: Tara
authors.initials: T
authors.lastname: Mirto
authors.forename: Jessica
authors.initials: J
authors.lastname: Martin
authors.forename: Allison
authors.initials: A
authors.lastname: Clarke
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Fischman
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism*; D002250:Carbon Radioisotopes; D003042:Cocaine / Q000031:analogs & derivatives*; D003692:Delayed-Action Preparations / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D064699:Dexmethylphenidate Hydrochloride; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D008774:Methylphenidate / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D008875:Middle Aged; D049268:Positron-Emission Tomography / Q000379:methods*; D011869:Radioligand Assay / Q000379:methods
chemical_list: D002250:Carbon Radioisotopes; D003692:Delayed-Action Preparations; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; C102282:N-iodoallyl-2-carbomethoxy-3-(4-fluorophenyl)tropane; D064699:Dexmethylphenidate Hydrochloride; D008774:Methylphenidate; D003042:Cocaine