Sage Journals: Discover world-class research

Abstract

For abuse potential assessment, U.S. Food and Drug Administration (FDA) requests that new, brain-penetrating drugs are ideally compared with approved drugs that share the mechanism of action and are judged to have abuse liability by the Drug Enforcement Agency. For development of the dual orexin receptor antagonist (DORA) daridorexant, the FDA recommended conducting a rat drug discrimination paradigm against the approved, schedule IV, DORA suvorexant. Surprisingly, at suvorexant plasma levels up to three-fold the maximum concentration at the highest approved human dose, rats did not learn to discriminate the suvorexant stimulus from vehicle.

Keywords

Rat suvorexant drug discrimination dual orexin receptor antagonist discriminative stimulus

Get full access to this article

View all access options for this article.

References

Born

Gauvin

Mukherjee

, et al (2017) Preclinical assessment of the abuse potential of the orexin receptor antagonist, suvorexant. Regul Toxicol Pharmacol 86: 181–192.

FDA (2014), Approval letter suvorexant. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/204569Orig1s000Approv.pdf (accessed 13 August 2023).

FDA (2017), Guidance document on the assessment of abuse potential of drugs. Available at: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/assessment-abuse-potential-drugs (accessed 30 August 2023).

Mignot

Mayleben

Fietze

, et al (2022) Safety and efficacy of daridorexant in patients with insomnia disorder: results from two multicentre, randomised, double-blind, placebo-controlled, phase 3 trials. Lancet Neurol 21: 125–139.

Rosenberg

Benca

Doghramji

, et al (2023) A 2023 update on managing insomnia in primary care: Insights from an expert consensus group. Prim Care Companion CNS Disord 25: 22nr03385.

Solinas

Panlilio

Justinova

, et al (2006) Using drug-discrimination techniques to study the abuse-related effects of psychoactive drugs in rats. Nat Protoc 1: 1194–1206.

Steiner

Lecourt

Strasser

, et al (2011) Differential effects of the dual orexin receptor antagonist almorexant and the GABA(A)-alpha1 receptor modulator zolpidem, alone or combined with ethanol, on motor performance in the rat. Neuropsychopharmacology 36: 848–856.

Treiber

de Kanter

Roch

, et al (2017) The use of physiology-based pharmacokinetic and pharmacodynamic modeling in the discovery of the dual orexin receptor antagonist ACT-541468. J Pharmacol Exp Ther 362: 489–503.

Winrow

Gotter

Cox

, et al (2011) Promotion of sleep by suvorexant-a novel dual orexin receptor antagonist. J Neurogenet 25: 52–61.

10.

Yee

McCrea

Panebianco

, et al (2018) Safety, tolerability, and pharmacokinetics of suvorexant: A randomized rising-dose trial in healthy men. Clin Drug Investig 38: 631–638.

11.

Young

(1991) Discriminative stimulus properties of benzodiazepines and several new anxiolytics. NIDA Res Monogr 116: 117–130.

Supplementary Material

Please find the following supplemental material available below.

For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.

For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.

0.02 MB

0.00 MB