Delving into the Latest Updates on Vornorexant with Synapse

AbstractWe investigated the metabolism and disposition of vornorexant, a novel dual orexin receptor antagonist, in rats and dogs, and clarified in vitro metabolite profiles in humans. Furthermore, we investigated the pharmacokinetics of active metabolites in rats and dogs and their CNS distribution in rats to elucidate its contribution to drug efficacy. [14C]vornorexant was rapidly and mostly absorbed after the oral administration in rats and dogs. The drug‐derived radioactivity, including metabolites, was distributed to major organs such as the liver, kidneys in rats, and was almost eliminated within 24 h post‐dose in both species. Metabolite profiling revealed that main clearance mechanism of vornorexant was metabolism via multiple pathways by oxidation. The major circulating components were the cleaved metabolites (M10, M12) in rats, and the unchanged form in dogs, followed by M1, and then M3. Incubation with human hepatocytes resulted in formation of metabolites, including M1, M3, M10, and M12. The metabolic pathways were similar in all tested species. Resulting from the PK and CNS distribution of active metabolites (M1 and M3) with weaker pharmacological activity, the concentration of the unchanged form was higher than that of active metabolites in rat CSF and dog plasma, suggesting that the unchanged form mainly contributed to the drug efficacy. These findings demonstrate that vornorexant is absorbed immediately after administration, and vornorexant and its metabolites are rapidly and completely eliminated in rats and dogs. Thus, vornorexant may have favorable pharmacokinetic profiles as a hypnotic drug to provide rapid onset of action and minimal next‐day residual effects in humans.

01 Nov 2023·Basic & clinical pharmacology & toxicology

Pharmacokinetics, pharmacodynamics and safety profile of the dual orexin receptor antagonist vornorexant/TS-142 in healthy Japanese participants following single/multiple dosing: Randomized, double-blind, placebo-controlled phase-1 studies.

Article

Author: Konno, Yoshihiro ; Matsushita, Isao ; Imadera, Yumiko ; Mano, Yoko ; Kambe, Daiji ; Uchiyama, Makoto ; Ogo, Hiroki ; Uchimura, Naohisa ; Hasegawa, Sayaka

The pharmacokinetics, pharmacodynamics and safety profile of vornorexant were investigated in healthy Japanese participants in three double-blind studies: a single ascending dose of 1-30 mg (Study 101; n = 6) and multiple ascending doses of 10-30 mg (Study 102; n = 6). Study 202 consisted of two steps: an open-label, 20 mg repeated-dose in non-elderly individuals (Step 1; n = 12) and a double-blind, 20 mg repeated-dose in elderly individuals (Step 2; n = 8/3 for vornorexant/placebo). Vornorexant was rapidly absorbed and eliminated under fasting conditions, with a time to maximum plasma concentration of 0.500-3.00 h (range) and elimination half-life of 1.32-3.25 h. The area under the plasma concentration-time curve (AUC) of vornorexant increased proportionally with dose increments. Sleepiness-related pharmacodynamic outcome changes (Karolinska sleepiness scale, digit symbol substitution test and psychomotor vigilance task) were generally increased with dose increments at 1 and 4 h post-dose, whereas no consistent dose-related changes were detected the next morning. Food intake did not affect the maximum observed plasma concentration of vornorexant but increased the AUC_0-inf . Exposure in elderly individuals was generally comparable to that in non-elderly individuals. Altogether, vornorexant may have a favourable profile for insomnia treatment, including rapid onset of action and minimal next-day residual effects.

01 Jan 2023·Archives of Neuropsychiatry

Orexin Receptor Antagonists as an Adjunct for the Treatment of Depression: A mini meta-analysis

Review

Author: Uğurlu, Mustafa

IntroductionThere is growing interest in the efficacy of orexin receptor antagonists (ORA), one of the new psychopharmacological agents used in the treatment of insomnia, in other psychiatric disorders such as depression.MethodsThis meta-analysis was conducted in accordance with PRISMA requirements. Literature searches were conducted using PubMed, Scopus and EBSCO (Medline) databases. Search words were (depression OR mood disorder OR affective disorder) AND (orexin OR orx OR hypocretin OR orx1 OR orx2 OR orexin receptor antagonist OR almorexant OR suvorexant OR lemborexant OR daridorexant OR seltorexant OR vornorexant OR filorexant). No date restrictions were used. The random effects model was used for analyses with I² values above 50% and fixed effects model was used for analyses with I² values below 50%.ResultsIn the acute phase, ORAs had no significant effect on core, sleep-adjusted and total symptoms of depression respectively; Standardized Mean Difference (SMD) for random effect -0.422, 95% CI [-0.90; 0.06], p=0.089, I²=62.4%; SMD for random effect -0.375, 95% CI [-1.24; 0.49], p=0.400; I²=66.6% and SMD for random effect -0.477, 95% CI [-0.97; 0.01], p=0.059; I²=83.1%). However, they had a significant effect on core and total symptoms of depression in the early period respectively; SMD for fixed effect=-0.228, 95% CI [-0.44; -0.01], p=0.036, I²=9.1%; and SMD for fixed effect=-0.186, 95% CI [-0.37; -0.001], p=0.048, I²=0.0%, respectively).ConclusionThe results of this meta-analysis suggest that ORAs may provide direct antidepressant efficacy when added to existing antidepressant treatment and may also have indirect antidepressant effects through improvement in sleep symptoms. Considering the physiological effects of orexin on behaviors, ORAs may be promising new treatment modalities in the treatment of many psychiatric disorders other than insomnia. However, these results are preliminary and further studies with different ORAs at different doses and with different samples are needed.

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Indication	Highest Phase	Country/Location	Organization	Date
Sleep Initiation and Maintenance Disorders	Phase 3	JP	Taisho Pharmaceutical Co., Ltd.	30 Aug 2022
Liver Injury	Phase 1	JP	Taisho Pharmaceutical Co., Ltd.	26 Dec 2022
Obstructive Sleep Apnea Hypopnea Syndrome	Preclinical	JP	Taisho Pharmaceutical Co., Ltd.	24 Feb 2021