Administration of oxathridine, a first‐in‐class histamine‐3 receptor partial agonist in healthy male volunteers: Central nervous system depression and pseudo‐hallucinations

Aims To characterise the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of single ascending doses of oxathridine, a first‐in‐class histamine‐3 receptor partialagonist, in healthy male volunteers. Methods A randomised, double‐blind, placebo‐controlled study including the NeuroC...

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Published in:British journal of clinical pharmacology 2024-01, Vol.90 (1), p.321-335
Main Authors: Dijkstra, Francis M., Zuiker, Rob G. J. A., Heuberger, Jules A. A. C., Kanhai, Kawita M. S., De Kam, Marieke, Duvauchelle, Thierry, Lecomte, Jeanne‐Marie, Labeeuw, Olivier, Landais, Laurent, Ligneau, Xavier, Robert, Philippe, Capet, Marc, Schwartz, Jean‐Charles, Gerven, Joop M. A.
Format: Article
Language:English
Subjects:
Central Nervous System
Depression
Dose-Response Relationship, Drug
Double-Blind Method
Electroencephalography
first‐in‐man
Hallucinations
Healthy Volunteers
Histamine
histamine‐3 partial agonist
Humans
Male
pharmacodynamics
pharmacokinetics
tolerability
translatability
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Summary:Aims To characterise the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of single ascending doses of oxathridine, a first‐in‐class histamine‐3 receptor partialagonist, in healthy male volunteers. Methods A randomised, double‐blind, placebo‐controlled study including the NeuroCart, consisting of a battery of drug sensitive neurophysiological tests, was performed. Oxathridine was administered orally as an aqueous solution. After dosing, safety and NeuroCart tests (adaptive tracking [AT], body sway [BS], saccadic peak velocity [SPV], smooth pursuit [SP] eye movements, VAS according to Bond and Lader, VAS according to Bowdle [VAS B&L, Bowdle], pharmaco‐electroencephalogram [pEEG], Sustained Attention to Response Task [SART]) were performed at set times. Results   Forty volunteers completed the study. Given doses were: 0.5, 2.5, 5, 0.25 and 1.5 mg. At 5 mg, unacceptable and unanticipated adverse events (AEs) of (orthostatic) hypotension and pseudo‐hallucinations were reported. Statistically significant effects ([CI]; p‐value) of 2.5 mg and 5 mg oxathridine were observed on AT ([−8.28, −1.60]; p = 0.0048), ([−8.10, −1.51]; p = 0.00530), BS ([0.6, 80.2]; p = 0.0455), ([5.9, 93.1]; p = 0.0205) and SPV ([−59.0, −15.9]; p = 0.0011), ([−43.9, −1.09]; p = 0.0399), respectively. Oxathridine 5 mg significantly increased all three VAS Bowdle subscale scores; VAS external ([0.183, 0.476]; p =
ISSN:0306-5251
1365-2125
DOI:10.1111/bcp.15910