Up to 40% of patients suffering from anxiety disorders do not benefit from currently available pharmacological treatments. Overactivity of the orexin-1 receptor (OX1R) has been implicated in anxiety- and panic-related states.
Aim & methods:
We investigated the pharmacokinetics and characterized the pharmacodynamic (PD) profile of the OX1R antagonist JNJ-61393215 using a battery of central nervous system assessments investigating relevant functional domains such as alertness, attention, (visuo)motor coordination, balance, subjective effects and resting-state electroencephalography in a single ascending dose placebo-controlled study in doses from 1 to 90 mg inclusive, assessing PD up to 10 h after dosing, safety and pharmacokinetic in 48 healthy male subjects.
Results:
Average time to maximal plasma concentration (Tmax) ranged between 1.0 and 2.25 h; average half-life ranged from 13.6 to 24.6 h and average maximum plasma concentration ranged from 1.4 to 136.8 ng/mL in the 1 and 90 mg groups, respectively. JNJ-61393215 did not demonstrate any statistically significant or clinically meaningful effects on any PD endpoint at any dose investigated at Tmax nor over the total period up to 10 h post-dose and was well tolerated. The reported somnolence rate was 16.7% (which was attributable to the cohorts receiving 6 mg and higher doses) compared to 12.5% in placebo.
Conclusion:
This observation is in line with our knowledge about the OX1R in preclinical studies, where only inconsistent and non-dose-dependent changes in electroencephalography or other behavioural measures were observed under non-challenged conditions, potentially exemplifying the need for a challenged subject.
American Psychiatric Association (2013) Diagnostic and Statistical Manual of Mental Disorders. Washington, DC: American Psychiatric Association.
2.
ArendtDHHassellJLiH, et al. (2014) Anxiolytic function of the orexin 2/hypocretin A receptor in the basolateral amygdala. Psychoneuroendocrinology40(1): 17–26.
3.
BaakmanACZuikerRVan GervenJMA, et al. (2019) Central nervous system effects of the histamine-3 receptor antagonist CEP-26401, in comparison with modafinil and donepezil, after a single dose in a cross-over study in healthy volunteers. Br J Clin Pharmacol85(5): 970–985.
4.
BaasJMPMolNKenemansJL, et al. (2009) Validating a human model for anxiety using startle potentiated by cue and context: The effects of alprazolam, pregabalin, and diphenhydramine. Psychopharmacology205(1): 73–84.
5.
BaldwinDSAndersonIMNuttDJ, et al. (2014) Evidence-based pharmacological treatment of anxiety disorders, post-traumatic stress disorder and obsessive-compulsive disorder: A revision of the 2005 guidelines from the British Association for Psychopharmacology. J Psychopharmacol28(5): 403–439.
6.
BalohRWSillsAWKumleyWE, et al. (1975) Quantitative measurement of saccade amplitude, duration, and velocity. Neurology25(11): 1065–1070.
7.
BonaventurePDugovicCShiremanB, et al. (2017) Evaluation of JNJ-54717793 a novel brain penetrant selective orexin 1 receptor antagonist in two rat models of panic attack provocation. Front Pharmacol8: 357.
8.
BonaventurePSheltonJYunS, et al. (2015) Characterization of JNJ-42847922, a selective orexin-2 receptor antagonist, as a clinical candidate for the treatment of insomnia. J Pharmacol Exp Ther354(3): 471–482.
9.
BondALaderM (1974) The use of analogue scales in rating subjective feelings. Psychol Psychother Theor, Res Prac47(3): 211–218.
10.
BonnavionPJacksonACCarterME, et al. (2015) Antagonistic interplay between hypocretin and leptin in the lateral hypothalamus regulates stress responses. Nat Commun6: 6266.
11.
BorlandRNicholsonA (1984) Visual motor co-ordination and dynamic visual acuity. Br J Clin Pharmacol18(1S): 69S–72S.
12.
BowdleTARadantADCowleyDS, et al. (1998) Psychedelic effects of ketamine in healthy volunteers: Relationship to steady-state plasma concentrations. Anesthesiology88(1): 82–88.
ChenXBroeyerFDe KamM, et al. (2017) Pharmacodynamic response profiles of anxiolytic and sedative drugs. Br J Clin Pharmacol83(5): 1028–1038.
15.
ChenXDe HaasSDe KamM, et al. (2012) An overview of the CNS-pharmacodynamic profiles of nonselective and selective GABA agonists. Adv Pharmacol Sci2012: 134523.
16.
ChenXJacobsGDe KamM, et al. (2014) The central nervous system effects of the partial GABA-Aα2,3-selective receptor modulator AZD7325 in comparison with lorazepam in healthy males. Br J Clin Pharmacol78(6): 1298–1314.
17.
ChenXJacobsGDe KamML, et al. (2015) AZD6280, a novel partial γ-aminobutyric acid a receptor modulator, demonstrates a pharmacodynamically selective effect profile in healthy male volunteers. J Clin Psychopharmacol35(1): 22–33.
18.
ChenXVan GervenJCohenA, et al. (2019) Human pharmacology of positive GABA-A subtype-selective receptor modulators for the treatment of anxiety. Acta Pharmacol Sinica40(5): 571–582.
19.
CruzHGHayJLHoeverP, et al. (2014) Pharmacokinetic and pharmacodynamic interactions between almorexant, a dual orexin receptor antagonist, and desipramine. Eur Neuropsychopharmacol24(8): 1257–1268.
20.
De HaasSLDe VisserSJVan Der PostJP, et al. (2007) Pharmacodynamic and pharmacokinetic effects of TPA023, a GABAA α2,3 subtype-selective agonist, compared to lorazepam and placebo in healthy volunteers. J Psychopharmacol21(4): 374–383.
21.
De HaasSLDe VisserSJVan Der PostJP, et al. (2008) Pharmacodynamic and pharmacokinetic effects of MK-0343, a GABAA α2,3 subtype selective agonist, compared to lorazepam and placebo in healthy male volunteers. J Psychopharmacol22(1): 24–32.
22.
De HaasSLFransonKLSchmittJAJ, et al. (2009) The pharmacokinetic and pharmacodynamic effects of SL65.1498, a GABA-A 2,3 selective agonist, in comparison with lorazepam in healthy volunteers. J Psychopharmacol23(6): 625–632.
23.
FarachFJPruittLDJunJJ, et al. (2012) Pharmacological treatment of anxiety disorders: Current treatments and future directions. J Anxiety Disord26(8): 833–43.
24.
FeltenDLSladekJR (1983) Monoamine distribution in primate brain V. Monoaminergic nuclei: Anatomy, pathways and local organization. Brain Res Bull10(2): 171–284.
25.
FergusonJM (2001) SSRI antidepressant medications: Adverse effects and tolerability. Prim Care Comp J Clin Psychiatry3(1): 22–27.
26.
GroeneveldGJHayJLVan GervenJM (2016) Measuring blood–brain barrier penetration using the NeuroCart, a CNS test battery. Drug Discov Today Technol20: 27–34.
27.
HeubergerJZuikerRLabeeuwO, et al. (2016) The histamine H3-receptor partial agonist Oxathridine shows sedative effects but also pseudo-hallucinations: First-in-human randomized, placebo controlled, SAD study in healthy volunteers. Inflamm Res65(1): S31.
28.
HeydendaelWSenguptaABeckS, et al. (2014) Optogenetic examination identifies a context-specific role for orexins/hypocretins in anxiety-related behavior. Physiol Behav130: 182–190.
29.
HochMVan GorselHVan GervenJ, et al. (2014) Entry-into-humans study with ACT-462206, a novel dual orexin receptor antagonist, comparing its pharmacodynamics with almorexant. J Clin Pharmacol54(9): 979–986.
30.
HoeverPDe HaasSWinklerJ, et al. (2010) Orexin receptor antagonism, a new sleep-promoting paradigm: An ascending single-dose study with almorexant. Clin Pharmacol Ther87(5): 593–600.
31.
HoeverPDe HaasSLDorffnerG, et al. (2012a) Orexin receptor antagonism: An ascending multiple-dose study with almorexant. J Psychopharmacol26(8): 1071–1080.
32.
HoeverPDe HaasSLDorffnerG, et al. (2012b) Orexin receptor antagonism: An ascending multiple-dose study with almorexant. J Psychopharmacol26(8): 1071–1080.
33.
HoeverPHayJRadM, et al. (2013) Tolerability, pharmacokinetics, and pharmacodynamics of single-dose almorexant, an orexin receptor antagonist, in healthy elderly subjects. J Clin Psychopharmacol33(3): 363–370.
34.
HuizingaCRHZuikerRGDe KamML, et al. (2019) Evaluation of simulated driving in comparison to laboratory-based tests to assess the pharmacodynamics of alprazolam and alcohol. J Psychopharmacol (Oxford, England)33(7): 791–800.
35.
JohnsonPSamuelsBFitzS, et al. (2012) Orexin 1 receptors are a novel target to modulate panic responses and the panic brain network. Physiol Behav107(5): 733–742.
36.
JohnsonPSamuelsBFitzSLightmanS, et al. (2012) Activation of the orexin 1 receptor is a critical component of CO2-mediated anxiety and hypertension but not bradycardia. Neuropsychopharmacology37(8): 1911–1922.
37.
JohnsonPLTruittWFitzSD, et al. (2010) A key role for orexin in panic anxiety. Nat Med16(1): 111–115.
38.
KaufmannPOrtMGolorG, et al. (2020) First-in-human study with ACT-539313, a novel selective orexin-1 receptor antagonist. Br J Clin Pharmacol86(7): 1377–1386.
39.
LiBChangLPengX (2021) Orexin 2 receptor in the nucleus accumbens is critical for the modulation of acute stress-induced anxiety. Psychoneuroendocrinology131: 105317.
40.
MaJSvetnikVSnyderE, et al. (2014) Electroencephalographic power spectral density profile of the orexin receptor antagonist suvorexant in patients with primary insomnia and healthy subjects. Sleep37(10): 1609–1619.
41.
MarcusJNAschkenasiCJLeeCE, et al. (2001) Differential expression of Orexin receptors 1 and 2 in the rat brain. J Comp Neurol435(1): 6–25.
42.
MuehlanCBoehlerMBrooksS, et al. (2019) 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. J Psychopharmacol (Oxford, England)34(3): 326–335. DOI: 269881119882854.
43.
MuehlanCBrooksSZuikerR, et al. (2019) Multiple-dose clinical pharmacology of ACT-541468, a novel dual orexin receptor antagonist, following repeated-dose morning and evening administration. Eur Neuropsychopharmacol29(7): 847–857.
44.
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(5): 1022–1029.
45.
SakuraiT (2007) The neural circuit of orexin (hypocretin): maintaining sleep and wakefulness. Nat Rev Neurosci8(3): 171–181.
46.
SalomonRMRipleyBKennedyJS, et al. (2003) Diurnal variation of cerebrospinal fluid hypocretin-1 (Orexin-A) levels in control and depressed subjects. Biol Psychiatry54(2): 96–104.
47.
SalvadoreGBonaventurePShekharA, et al. (2020) Translational evaluation of novel selective orexin-1 receptor antagonist JNJ-61393215 in an experimental model for panic in rodents and humans. Transl Psychiatry10(1): 1–10.
48.
StatonCDYaegerJDWKhalidD, et al. (2018) Orexin 2 receptor stimulation enhances resilience, while orexin 2 inhibition promotes susceptibility, to social stress, anxiety and depression. Neuropharmacology143: 79–94.
49.
SturzeneggerCBaumannCRLammersGJ, et al. (2018) Swiss Narcolepsy Scale: A simple screening tool for hypocretin-deficient narcolepsy with cataplexy. Clin Transl Neurosci2(2): 1–5. DOI: 2514183X1879417.
50.
SuzukiMBeuckmannCTShikataK, et al. (2005) Orexin-A (hypocretin-1) is possibly involved in generation of anxiety-like behavior. Brain Res1044(1): 116–121.
51.
TaylorSAbramowitzJSMcKayD (2012) Non-adherence and non-response in the treatment of anxiety disorders. J Anxiety Disord26(5): 583–589.
52.
Van AmerongenGSiebengaPSGurrellR, et al. (2019) Analgesic potential of PF-06372865, an α2/α3/α5 subtype-selective GABAA partial agonist, in humans. Br J Anaesth123(2): e194–e203.
53.
Van der ArkPDGolorGVan NuetenL, et al. (2018) Multiple daytime administration of the selective orexin-2 receptor antagonist JNJ-42847922 induces somnolence in healthy subjects without residual central effects. J Psychopharmacolgy32(12): 1330–1340.
54.
WebsterKCellaDYostK (2003) The functional assessment of chronic illness therapy (FACIT) measurement system: Properties, applications, and interpretation. Health Qual Life Outcomes1: 79.
55.
WrightBM (1971) A simple mechanical ataxia-meter. J Physiol218(1): 27P–28P.
56.
ZuikerRGJAChenXØsterbergO, et al. (2016) NS11821, a partial subtype-selective GABAA agonist, elicits selective effects on the central nervous system in randomized controlled trial with healthy subjects. J Psychopharmacol30(3): 253–262.
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.
