Restricted accessResearch articleFirst published online 2020-3
Clinical pharmacology of the dual orexin receptor antagonist ACT-541468 in elderly subjects: Exploration of pharmacokinetics,pharmacodynamics and tolerability following single-dose morning and repeated-dose evening administration
The dual orexin receptor antagonist ACT-541468 showed sedative pharmacodynamic effects during initial clinical testing in adult subjects. The present study explored pharmacokinetics, pharmacodynamics and tolerability in healthy elderly subjects.
Methods:
Double-blind, placebo-controlled, randomised, single-ascending dose study in 24 male/female elderly (65–80 years, 5, 15 and 25 mg in the morning, 6/2 active/placebo per group). Additionally, 10 subjects (8/2 active/placebo) received 25 mg for 7 days in the evening. Pharmacokinetics, pharmacodynamics (saccadic peak velocity, adaptive tracking, body sway, visual analogue scales according to Bowdle and Bond and Lader, Karolinska Sleepiness Scale) and tolerability were assessed. In particular, pharmacodynamics results are to be interpreted exploratorily.
Results:
Absorption was quick with a median time to maximum concentration of ∼ 1.0 h. The mean elimination half-life was 8.5–9.8 h, the area under the curve and the maximum plasma concentration increased proportionally with dose. Following repeated evening administration of 25 mg, minimal accumulation was observed. There were no pharmacodynamic effects at 5 mg. At 15 mg, saccadic peak velocity (degree/s; SD) was reduced (69; 38), while other variables showed no effects. At 25 mg, effects on all objective pharmacodynamic parameters were observed. At 8–12 h post-dose, there were no differences to placebo and no next-day effects on pharmacodynamic variables after evening administration. Elderly subjects reported fewer adverse events compared to adults in previous studies.
Conclusion:
ACT-541468 in elderly subjects was well tolerated and pharmacokinetics and pharmacodynamics are compatible with a drug for the treatment of insomnia.
AbadVCGuilleminaultC (2018) Insomnia in elderly patients: Recommendations for pharmacological management. Drugs Aging35: 791–817.
2.
AgostiniJVHanLTinettiME (2004) The relationship between number of medications and weight loss or impaired balance in older adults. J Am Geriatr Soc52: 1719–1723.
3.
ÅkerstedtTGillbergM (1990) Subjective and objective sleepiness in the active individual. Int J Neurosci52: 29–37.
4.
American Psychiatric Association (2013) Diagnostic and Statistical Manual of Mental Disorders (DSM-5®). 5th ed.Washington, DC: American Psychiatric Publishing.
5.
Ancoli-IsraelS (2009) Sleep and its disorders in aging populations. Sleep Med10: S7–S11.
6.
AvidanAYFriesBEJamesML, et al. (2005) Insomnia and hypnotic use, recorded in the minimum data set, as predictors of falls and hip fractures in Michigan nursing homes. J Am Geriatr Soc53: 955–962.
7.
BencaRMAncoli-IsraelSMoldofskyH (2004) Special considerations in insomnia diagnosis and management: Depressed, elderly, and chronic pain populations. J Clin Psychiatry65: 26–35.
8.
BondALaderM (1974) The use of analogue scales in rating subjective feelings. Br J Med Psychol47: 211–218.
9.
BoofMLAlatrachAUferM, et al. (2018) Interaction potential of the dual orexin receptor antagonist ACT-541468 with CYP3A4 and food: Results from two interaction studies. Eur J Clin Pharmacol75: 195–205.
10.
BorlandRGNicholsonAN (1984) Visual motor co-ordination and dynamic visual acuity. Br J Clin Pharmacol18: 69S–72S.
11.
BowdleATRadantADCowleyDS, et al. (1998) Psychedelic effects of ketamine in healthy volunteers: Relationship to steady-state plasma concentrations. Anesthesiology88: 82–88.
12.
Brisbare-RochCDingemanseJKobersteinR, et al. (2007) Promotion of sleep by targeting the orexin system in rats, dogs and humans. Nat Med13: 150–155.
13.
ButlerJMBeggEJ (2008) Free drug metabolic clearance in elderly people. Clin Pharmacokinet47: 297–321.
14.
ChongYFryarCGuQ (2013) Prescription Sleep Aid Use Among Adults: United States, 2005–2010. NCHS Data Brief 2013. Hyattsville, MD: US Department of Health and Human Services, CDC, National Center for Health Statistics.
15.
CotreauMMvon MoltkeLLGreenblattDJ (2005) The influence of age and sex on the clearance of cytochrome P450 3A substrates. Clin Pharmacokinet44: 33–60.
16.
de HaasSLSchoemakerRCVan GervenJMA, et al. (2010) Pharmacokinetics, pharmacodynamics and the pharmacokinetic/pharmacodynamic relationship of zolpidem in healthy subjects. J Psychopharmacol24: 1619–1629.
17.
de LeceaLKilduffTSPeyronC, et al. (1998) The hypocretins: Hypothalamus-specific peptides with neuroexcitatory activity. Proc Natl Acad Sci USA95: 322–327.
18.
DurnasCLoiCMCusackBJ (1990) Hepatic drug metabolism and aging. Clin Pharmacokinet19: 359–389.
19.
EllisJGPerlisMLNealeLF, et al. (2012) The natural history of insomnia: Focus on prevalence and incidence of acute insomnia. J Psychiatr Res46: 1278–1285.
20.
FordDEKamerowDB (1989) Epidemiologic study of sleep disturbances and psychiatric disorders: An opportunity for prevention?JAMA262: 1479–1484.
21.
GillbergMKecklundGÅkerstedtT (1996) Sleepiness and performance of professional drivers in a truck simulator: Comparisons between day and night driving. J Sleep Res5: 12–15.
22.
GoughKHutchisonMKeeneO, et al. (1995) Assessment of dose proportionality: Report from the statisticians in the pharmaceutical industry/pharmacokinetics UK joint working party. Drug Info J29: 1039–1048.
23.
GrünbergerJLinzmayerLDietzelM, et al. (1993) The effect of biologically-active light on the noo-and thymopsyche and on psychophysiological variables in healthy volunteers. Int J Psychophysiol15: 27–37.
24.
HoeverPde HaasSWinklerJ, et al. (2010) Orexin receptor antagonism, a new sleep-promoting paradigm: An ascending single-dose study with almorexant. Clin Pharmacol Ther87: 593–600.
25.
HoeverPde HaasSLDorffnerG, et al. (2012) Orexin receptor antagonism: An ascending multiple-dose study with almorexant. J Psychopharmacol26: 1071–1080.
26.
HoyerDJacobsonLH (2013) Orexin in sleep, addiction and more: Is the perfect insomnia drug at hand?Neuropeptides47: 477–488.
MahlerSVMoormanDESmithRJ, et al. (2014) Motivational activation: A unifying hypothesis of orexin/hypocretin function. Nat Neurosci17: 1298–1303.
29.
McCallWV (2004) Sleep in the elderly: Burden, diagnosis, and treatment. Prim Care Companion J Clin Psychiatry6: 9–20.
30.
MetsMAVolkertsEROlivierB, et al. (2010) Effect of hypnotic drugs on body balance and standing steadiness. Sleep Med Rev14: 259–267.
31.
MichelsonDSnyderEParadisE, et al. (2014) Safety and efficacy of suvorexant during 1-year treatment of insomnia with subsequent abrupt treatment discontinuation: A phase 3 randomised, double-blind, placebo-controlled trial. Lancet Neurol13: 461–471.
32.
MuehlanCBrooksSZuikerR, et al. (2019b) Multiple-dose clinical pharmacology of ACT-541468, a novel dual orexin receptor antagonist, following repeated-dose morning and evening administration. Eur Neuropsychopharmacol29: 847–857.
33.
MuehlanCFischerHZimmerD, et al. (2019a) Metabolism of the Dual Orexin Receptor Antagonist ACT-541468, Based on Microtracer/Accelerator Mass Spectrometry. Curr Drug Metab20: 253–265.
34.
MuehlanCHeubergerJJuifPE, et al. (2018) Accelerated development of the dual orexin receptor antagonist ACT-541468: Integration of a microtracer in a first-in-human study. Clin Pharmacol Ther104: 1022–1029.
35.
OhayonMM (2009) Observation of the natural evolution of insomnia in the American general population cohort. Sleep Med Clin4: 87–92.
36.
OhayonMMReynoldsCF (2009) Epidemiological and clinical relevance of insomnia diagnosis algorithms according to the DSM-IV and the International Classification of Sleep Disorders (ICSD). Sleep Med10: 952–960.
37.
OhayonMMSmirneS (2002) Prevalence and consequences of insomnia disorders in the general population of Italy. Sleep Med3: 115–120.
38.
OhayonMMVecchieriniMF (2005) Normative sleep data, cognitive function and daily living activities in older adults in the community. Sleep28: 981–989.
39.
OhayonMMZulleyJGuilleminaultC, et al. (2001) How age and daytime activities are related to insomnia in the general population: Consequences for older people. J Am Geriatr Soc49: 360–366.
40.
ReedTCarmelliDSwanGE, et al. (1994) Lower cognitive performance in normal older adult male twins carrying the apolipoprotein E 4 allele. Arch Neurol51: 1189–1192.
41.
RoeckerAJCoxCDColemanPJ (2015) Orexin receptor antagonists: New therapeutic agents for the treatment of insomnia. J Med Chem59: 504–530.
RowlandMTozerTNDerendorfH, et al. (2011) Clinical Pharmacokinetics and Pharmacodynamics: Concepts and Applications. Philadelphia, PA: Wolters Kluwer Health/Lippincott William & Wilkins.
44.
SakuraiT (2007) The neural circuit of orexin (hypocretin): Maintaining sleep and wakefulness. Nat Rev Neurosci8: 171–181.
45.
SakuraiTAmemiyaAIshiiM, et al. (1998) Orexins and orexin receptors: A family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell92: 573–585.
46.
SateiaMJBuysseDJKrystalAD, et al. (2017) Clinical practice guideline for the pharmacologic treatment of chronic insomnia in adults: An American Academy of Sleep Medicine clinical practice guideline. J Clin Sleep Med13: 307–349.
47.
SchlackRHapkeUMaskeU, et al. (2013) Frequency and distribution of sleep problems and insomnia in the adult population in Germany: Results of the German Health Interview and Examination Survey for Adults (DEGS1). Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz56: 740–748.
48.
Schutte-RodinSBrochLBuysseD, et al. (2008) Clinical guideline for the evaluation and management of chronic insomnia in adults. J Clin Sleep Med4: 487–504.
49.
SturzeneggerCBassettiCL (2004) The clinical spectrum of narcolepsy with cataplexy: A reappraisal. J Sleep Res13: 395–406.
50.
TreiberAde KanterRRochC, 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 Ther362: 489–503.
51.
van SteveninckALVan BerckelBNMSchoemakerRC, et al. (1999) The sensitivity of pharmacodynamic tests for the central nervous system effects of drugs on the effects of sleep deprivation. J Psychopharmacol13: 10–17.
52.
VersterJCSpenceDShahidA, et al. (2011) Zopiclone as positive control in studies examining the residual effects of hypnotic drugs on driving ability. Curr Drug Saf6: 209–218.
53.
WechslerD (1981) Manual for the Wechsler Adult Intelligence Scale-Revised. New York: Psychological Corporation.
54.
WrightBM (1971) A simple mechanical ataxia-meter. J Physiol218: 27P–28P.
55.
ZammitGWang-WeigandSRosenthalM, et al. (2009) Effect of ramelteon on middle-of-the-night balance in older adults with chronic insomnia. J Clin Sleep Med5: 34–40.
56.
ZuurmanLRoyCSchoemakerRC, et al. (2008) Effect of intrapulmonary tetrahydrocannabinol administration in humans. J Psychopharmacol22: 707–716.
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.
