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

• Published in: Journal of psychopharmacology (Oxford) Vol. 37; no. 6; p. 577
• Main Authors: Brooks, S, Zuiker, Rgja, Bleys, C, Ziagkos, D, Moyer, J A, van Nueten, L, Bonaventure, P, Drevets, W C, van Gerven, Jma, Salvadore, G, Jacobs, G E
• Format: Journal Article
• Language: English
• Published: United States 01.06.2023
• Subjects: Area Under Curve; Dose-Response Relationship, Drug; Double-Blind Method; Half-Life; Healthy Volunteers; Humans; Male; Orexin Receptor Antagonists - adverse effects; Orexin Receptor Antagonists - pharmacokinetics; Orexins; pharmacodynamics; Anxiety; orexin 1 antagonist
• ISSN: 1461-7285
• DOI: 10.1177/02698811231167989

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. 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. Average time to maximal plasma concentration ( ) 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 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. 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.