Single- and multiple-dose pharmacokinetics of samidorphan, a novel opioid antagonist, in healthy volunteers.

Abstract

PURPOSE:

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.

FINDINGS:

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.

IMPLICATIONS:

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: Ryan Turncliff, Lauren DiPetrillo, Bernard Silverman, Elliot Ehrich
• Journal: Clinical therapeutics (Clin Ther) Vol. 37 Issue 2 Pg. 338-48 (Feb 01 2015) ISSN: 1879-114X [Electronic] United States
• PMID: 25456560 (Publication Type: Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier HS Journals, Inc. All rights reserved.

Chemical References

• ALKS-33
• Morphinans
• Narcotic Antagonists
• Naltrexone
• 3-carboxamido-4-hydroxynaltrexone

Topics

• Administration, Oral
• Adult
• Area Under Curve
• Dose-Response Relationship, Drug
• Double-Blind Method
• Drug Administration Schedule
• Dyssomnias (chemically induced)
• Female
• Half-Life
• Healthy Volunteers
• Humans
• Male
• Middle Aged
• Morphinans (administration & dosage, adverse effects, pharmacokinetics)
• Naltrexone (administration & dosage, adverse effects, analogs & derivatives, pharmacokinetics)
• Narcotic Antagonists (administration & dosage, adverse effects, pharmacokinetics)