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Abuse potential assessment of the dual orexin receptor antagonist daridorexant in rats - PubMed

Abuse potential assessment of the dual orexin receptor antagonist daridorexant in rats

Michel A Steiner et al. J Psychopharmacol. 2023 Dec.

Abstract

Background: Drugs that act on the central nervous system (CNS) and have sedative effects can lead to abuse in humans. New CNS-active drugs often require evaluation of their abuse potential in dedicated animal models before marketing approval. Daridorexant is a new dual orexin receptor antagonist (DORA) with sleep-promoting properties in animals and humans. It was approved in 2022 in the United States and Europe for the treatment of insomnia disorder.

Aims: Nonclinical evaluation of abuse potential of daridorexant using three specific rat models assessing reinforcement, interoception, and withdrawal.

Methods: Reinforcing effects of daridorexant were assessed in an operant rat model of intravenous drug self-administration. Similarity of interoceptive effects to those of the commonly used sleep medication zolpidem was tested in an operant drug discrimination task. Withdrawal signs indicative of physical dependence were evaluated upon sudden termination of chronic daridorexant treatment. Rat experiments were conducted at a dose range resulting in daridorexant plasma concentrations equaling or exceeding those achieved at the clinically recommended dose of 50 mg in humans.

Results: Daridorexant had no reinforcing effects, was dissimilar to zolpidem in the drug discrimination task, and did not induce any withdrawal-related signs upon treatment discontinuation that would be indicative of physical dependence.

Outcomes: Daridorexant showed no signs of abuse or dependence potential in rats. Our data indicate that daridorexant, like other DORAs, has a low potential for abuse in humans.

Keywords: Self-administration; daridorexant; drug discrimination; dual orexin receptor antagonist; physical dependence.

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Conflict of interest statement

Declaration of conflicting interestsThe authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: MAS and MTS were employees and shareholders of Idorsia Pharmaceuticals Ltd at the time the study was conducted. Idorsia has developed daridorexant as a treatment for insomnia and is selling the drug under the trade name Quviviq®. MT, LD, and MEG have no conflicting interests to declare.

Figures

Figure 1.
Figure 1.

Active (a) and inactive (b) lever presses, and number of intravenous infusions (c) obtained during the baseline (sessions 1–3), substitution (sessions 1–6), and re-exposure (sessions 1–3) phase of the operant drug self-administration paradigm. N = 9 rats/treatment group. During baseline and re-exposure, all rats received cocaine. During the substitution phase (gray rectangle), cocaine was substituted with one of three doses of daridorexant or vehicle. One group remained on cocaine. Shown are group means ± SD (standard deviation). See the respective Results section for the statistical evaluation.

Figure 2.
Figure 2.

Percentage of responding on the zolpidem-appropriate lever (a) and response rate (b) during the entire test session following oral treatment with zolpidem, lorazepam, daridorexant, and suvorexant. Data points depicting the vehicle groups are slightly nudged for better visibility. Shown are group means ± SD (standard deviation). N = 9–11rats/treatment group. See the respective Results section for the statistical evaluation.

Figure 3.
Figure 3.

In the experiment assessing physical dependence (schematic in (a)), body weight (b), food consumption (FC) over 24 h (c), and body temperature (d) were monitored during baseline (D-1, for (b) and (d), D1 for (c); followed by a line break in the X axes), 28 days of oral vehicle or drug treatment, and 14 days after discontinuation of treatment (start of withdrawal phase indicated by a line break of the X-axis (b–d), and duration by the gray rectangle). Since FC is calculated over 24 h, the X-axis is shifted by one day for (c). The sudden and temporary drop of FC on Day 8 was likely related to a systemic error in the weighing procedure on that day. The scheme of blood sampling of satellite animals depicted in (a) only refers to daridorexant-treated rats. For better visibility, only group means are shown. For a figure with error bars depicting the standard deviation see

Supplemental Figure 4

. N = 10 rats/treatment group. See the respective Results section for statistical details. bid: twice daily; CDP: chlordiazepoxide; FOB: functional observation battery; PK: pharmacokinetic; qd: once daily; SLMA: spontaneous locomotor activity; WK: weeks.

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