title: Single- and multiple-dose pharmacokinetics of samidorphan, a novel opioid antagonist, in healthy volunteers.
abstract: OBJECTIVE
  Samidorphan (3-carboxamido-4-hydroxy naltrexone) is a novel opioid receptor antagonist that is currently in clinical development. The oral dose pharmacokinetics, safety, and tolerability of samidorphan were evaluated in 2 double-blind, placebo-controlled, randomized studies in healthy adults.
  
  
  METHODS
  The first study investigated single, ascending doses of 3.7 to 55.7 mg of samidorphan in 16 healthy adults; the second study evaluated multiple ascending doses of 10 or 20 mg of samidorphan administered for 7 days in 30 healthy adults.
  
  
  RESULTS
  Across the two studies, 39 of 46 subjects were male; 32 were white, 11 were black, and 3 were hispanic. Mean age was 34.9 years and mean weight was 84.2 kg. In both studies, samidorphan was rapidly absorbed, with a Tmax of 1 hour, and AUC increased with increasing dose. Samidorphan plasma levels declined in a monoexponential manner, with a half-life of ~7 to 9 hours. After multiple doses, steady state was approached by day 6 and achieved by day 7 after the 10-mg dose, but steady state was not reached for the 20-mg dose. Accumulation was low, with accumulation ratios <1.65. In both studies, samidorphan was generally well tolerated, with somnolence reported as the most common adverse event.
  
  
  CONCLUSIONS
  In these single- and multiple-dose studies in healthy volunteers, samidorphan exhibited a pharmacokinetic profile consistent with once-daily dosing. ClinicalTrials.gov identifier: NCT00800319.
authors.affiliation: Alkermes, Inc, Waltham, Massachusetts. Electronic address: ryan.turncliff@alkermes.com.
authors.forename: Ryan
authors.initials: R
authors.lastname: Turncliff
authors.affiliation: Alkermes, Inc, Waltham, Massachusetts.
authors.forename: Lauren
authors.initials: L
authors.lastname: DiPetrillo
authors.affiliation: Alkermes, Inc, Waltham, Massachusetts.
authors.forename: Bernard
authors.initials: B
authors.lastname: Silverman
authors.affiliation: Alkermes, Inc, Waltham, Massachusetts.
authors.forename: Elliot
authors.initials: E
authors.lastname: Ehrich
mesh_terms: D000284:Administration, Oral; D000328:Adult; D019540:Area Under Curve; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D020920:Dyssomnias / Q000139:chemically induced; D005260:Female; D006207:Half-Life; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D008875:Middle Aged; D009019:Morphinans / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D009271:Naltrexone / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D009292:Narcotic Antagonists / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*
chemical_list: C583425:ALKS-33; D009019:Morphinans; D009292:Narcotic Antagonists; D009271:Naltrexone; C000606131:3-carboxamido-4-hydroxynaltrexone
keywords: multiple ascending dose trial; opioid receptor antagonist; pharmacokinetics; safety; samidorphan; single ascending dose trial; tolerability