Tolerability, Pharmacokinetics, and Pharmacodynamics of Single-Dose Almorexant, an Orexin Receptor Antagonist, in Healthy Elderly Subjects

Abstract

Sleep disorders are common in the elderly population. Orexin receptor antagonism has been proposed as a new sleep-enabling approach to treat insomnia. The tolerability, pharmacokinetics, and pharmacodynamics of ascending single doses of almorexant, a dual orexin receptor antagonist, were investigated in healthy elderly male and female subjects. In this double-blind, placebo- and active-controlled study, each dose (100, 200, and 400 mg) was investigated in a separate group of 12 subjects (almorexant, placebo, and zolpidem 10 mg in an 8:2:2 ratio). Morning doses of almorexant were well tolerated. As expected for sleep-enabling compounds, somnolence and fatigue were frequently reported. Other adverse events included headache and nausea. Muscular weakness was reported at a higher incidence only with the highest almorexant dose. The pharmacokinetic profile of almorexant was characterized by a median time to the maximum concentration of 1.5 hours, quick disposition with a distribution half-life of 1.6 hours, and rapidly decreasing concentrations to approximately 20% of the maximum concentration over 8 hours, with a terminal half-life of 32 hours. Objective pharmacodynamic measures showed decreases in saccadic peak velocity and adaptive tracking performance and increases in body sway with the 400-mg dose of almorexant. Subjective assessments revealed a dose-dependent decrease in alertness. Almorexant had no effects on mood, calmness, subjective internal and external perception, and feeling high. These findings provide a solid basis to study the effects of almorexant in elderly patients with insomnia.

Orexin/Hypocretin Based Pharmacotherapies for the Treatment of Addiction: DORA or SORA?

“…Orexin antagonist effects on sleep architecture appear to be more idiosyncratic, with Suvorexant increasing REM sleep [187] while Actelion recently reported a DORA which increases NREM sleep in rats [188]. The hypnotic effects of orexin antagonists raises the possibility of cognitive impairment and some memory impairments have been observed in elderly patients given Almorexant [186]. However, studies on cognitive effects in rats have shown that DORAs have a relatively greater therapeutic window than current treatments for insomnia [189].…”

“…Animal studies have shown the importance of orexins for feeding [13,180], motivation [181], sleep/ wakefulness [182,183], male sexual behavior [98] and female proestrus [184] which raises the possibility of side effects such as anorexia, weight loss, anhedonia, and asexuality in addition to observed side effects such as somnolence, fatigue and muscle weakness [58,60,63,79,80,185,186]. Orexin antagonist effects on sleep architecture appear to be more idiosyncratic, with Suvorexant increasing REM sleep [187] while Actelion recently reported a DORA which increases NREM sleep in rats [188].…”

Therapeutic implications of the choroid plexus–cerebrospinal fluid interface in neuropsychiatric disorders

“…Interestingly, OXA was also detected in the areas surrounding the CP blood capillaries, suggesting that OXA levels in the CSF are probably regulated by CP activity (Tafuri et al, 2009). Several OXR antagonists effectively induce sleep in volunteers and insomnia patients (Equihua et al, 2013;Hoyer and Jacobson, 2013;Hoever et al, 2010Hoever et al, , 2012Hoever et al, , 2013Brisbare-Roch et al, 2007;Aissaoui et al, 2008). The development of these agents may lead to novel therapies for insomnia without the side effect profile of hypnotics, such as impaired cognition, disturbed arousal, and motor balance difficulties (Equihua et al, 2013).…”

Intrathecal Intermittent Orexin-A Causes Sympathetic Long-Term Facilitation and Sensitizes the Peripheral Chemoreceptor Response to Hypoxia in Rats

“…The pharmacokinetic profile of Almorexant is characterized by rapidly decreasing concentrations to approximately 20% of the maximum concentration over 8 hours, with a terminal half-life of 32 hours in humans (Hoever et al, 2013). In male canines, oral administration of Almorexant at a dose of 100 mg×kg 21 induced clinical signs of somnolence for up to Prolonged Sympathoexcitation by Repetitive Orexin-A 6 hours (Brisbare-Roch et al, 2007).…”