Leiden University Scholarly Publications

Persistent URL of this record https://hdl.handle.net/1887/3720682

In Collections

This item can be found in the following collections:

Brooks, S.; Zuiker, R.G.J.A.; Bleys, C.; Ziagkos, D.; Moyer, J.A.; Nueten, L. van; ... ; Jacobs, G.E. (2023)

Pharmacological characterization of the selective orexin-1 receptor antagonist JNJ-61393215 in healthy volunteers

Article / Letter to editor
Background: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...Show moreBackground: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.Show less
Anxiety
orexin 1 antagonist
pharmacodynamics
All authors
Brooks, S.; Zuiker, R.G.J.A.; Bleys, C.; Ziagkos, D.; Moyer, J.A.; Nueten, L. van; Bonaventure, P.; Drevets, W.C.; Gerven, J.M.A. van; Salvadore, G.; Jacobs, G.E.
Date
2023-05-11
Journal
Journal of Psychopharmacology
Volume
37
Issue
6
Pages
577 - 589
DOI
doi:10.1177/02698811231167989
Link
https://journals.sagepub.com/doi/10.1177/02698811231167989