title: Pharmacokinetics and Exposure-Response Relationships of Dasotraline in the Treatment of Attention-Deficit/Hyperactivity Disorder in Adults.
abstract: OBJECTIVE
  Dasotraline is a novel inhibitor of dopamine and norepinephrine reuptake currently being investigated in clinical studies for the treatment of attention-deficit/hyperactivity disorder (ADHD). Uniquely, relative to current ADHD medications, dasotraline has a slow absorption and long elimination half-life. Here we relate the pharmacokinetics and pharmacodynamics of dasotraline to reduction in ADHD symptoms based on simulated clinical trial outcomes.
  
  
  METHODS
  Dasotraline pharmacokinetics were analyzed by population pharmacokinetic methodologies using data collected from 395 subjects after single or multiple oral dose administrations ranging from 0.2 to 36 mg (three phase I studies and one phase II ADHD study). Population pharmacokinetic and pharmacodynamic models related individual dasotraline exposures to norepinephrine metabolite 3,4-dihydroxyphenylglycol (DHPG) concentrations, ADHD symptoms, and study discontinuation (probability of dropout).
  
  
  RESULTS
  Dasotraline pharmacokinetics were described by a one-compartment model with dual (linear plus nonlinear) elimination. In an ADHD population treated with dasotraline 4 or 8 mg/day, dasotraline was characterized by a mean apparent half-life of 47 h and plasma concentrations reached steady-state by 10 days of dosing. A population pharmacokinetic and pharmacodynamic model of DHPG indicated clinically significant norepinephrine transporter inhibition was achieved as a function of time-matched dasotraline concentrations. Dasotraline exposure reduced ADHD symptoms in a sigmoid E max time-course model. Clinical trial simulations described the effects of dose, duration, and sample size on clinical outcomes.
  
  
  CONCLUSIONS
  These results related dasotraline pharmacokinetics to pharmacological activity in ADHD, and support the novel concept that maintaining constant, steady-state dopamine and norepinephrine reuptake inhibition throughout a 24-h dosing interval is a novel pharmacological approach to the management of ADHD symptoms. Clinicaltrials.gov identifier: NCT01692782.
authors.affiliation: Sunovion Pharmaceuticals Inc., 84 Waterford Drive, Marlborough, MA, 01752, USA. seth.hopkins@sunovion.com.
authors.forename: Seth C
authors.initials: SC
authors.lastname: Hopkins
authors.affiliation: Sunovion Pharmaceuticals Inc., 84 Waterford Drive, Marlborough, MA, 01752, USA.
authors.forename: Soujanya
authors.initials: S
authors.lastname: Sunkaraneni
authors.affiliation: Sunovion Pharmaceuticals Inc., 84 Waterford Drive, Marlborough, MA, 01752, USA.
authors.forename: Estela
authors.initials: E
authors.lastname: Skende
authors.affiliation: Cognigen Corporation, Buffalo, NY, USA.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Hing
authors.affiliation: Cognigen Corporation, Buffalo, NY, USA.
authors.forename: Julie A
authors.initials: JA
authors.lastname: Passarell
authors.affiliation: Sunovion Pharmaceuticals Inc., 84 Waterford Drive, Marlborough, MA, 01752, USA.|Sunovion Pharmaceuticals Inc., Fort Lee, NJ, USA.
authors.forename: Antony
authors.initials: A
authors.lastname: Loebel
authors.affiliation: Sunovion Pharmaceuticals Inc., 84 Waterford Drive, Marlborough, MA, 01752, USA.
authors.forename: Kenneth S
authors.initials: KS
authors.lastname: Koblan
mesh_terms: D015057:1-Naphthylamine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D000284:Administration, Oral; D018759:Adrenergic Uptake Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D001289:Attention Deficit Disorder with Hyperactivity / Q000188:drug therapy* / Q000503:physiopathology; D017321:Clinical Trials, Phase I as Topic; D017322:Clinical Trials, Phase II as Topic; D018765:Dopamine Uptake Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D005260:Female; D006207:Half-Life; D006801:Humans; D008297:Male; D008734:Methoxyhydroxyphenylglycol / Q000031:analogs & derivatives / Q000378:metabolism; D008954:Models, Biological; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors; D016032:Randomized Controlled Trials as Topic
chemical_list: D018759:Adrenergic Uptake Inhibitors; D018765:Dopamine Uptake Inhibitors; D050484:Norepinephrine Plasma Membrane Transport Proteins; C000609455:4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-amine; D008734:Methoxyhydroxyphenylglycol; D015057:1-Naphthylamine; C010117:3,4-dihydroxyphenylglycol