Safety, tolerability, pharmacokinetics and pharmacokinetic-pharmacodynamic modelling of the novel H 4 receptor inhibitor SENS-111 using a modified caloric test in healthy subjects

Autor: Venail, Frederic, Attali, Pierre, Wersinger, Eric, Gomeni, Roberto, Poli, Sonia, Schmerber, Sébastien
Přispěvatelé: Service d'ORL, Hôpital Gui de Chauliac (CHRU de Montpellier), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Service d'Oto-Rhino-Laryngologie, CHU Grenoble
Jazyk: angličtina
Rok vydání: 2018
Předmět:
Zdroj: British Journal of Clinical Pharmacology
British Journal of Clinical Pharmacology, Wiley, 2018, 84 (12), pp.2836-2848. ⟨10.1111/bcp.13744⟩
ISSN: 0306-5251
1365-2125
DOI: 10.1111/bcp.13744⟩
Popis: International audience; AIM:A Phase 1 study was performed to evaluate safety, pharmacokinetics (PK) and pharmacodynamics (PD) of the selective histamine H4 receptor antagonist SENS-111, an oral small molecule.METHODS:One hundred healthy subjects were randomized in a placebo-controlled, double-blind study evaluating single-ascending doses (SAD; 100-500 mg) and multiple-ascending doses (MAD; 50-150 mg day-1 , 4 days; 200-250 mg day-1 , 7 days). Effects of SENS-111 on nystagmus and vertigo induced by modified caloric tests were measured in the MAD studies. Population PK and PK/PD models were developed using a nonlinear mixed-effects approach.RESULTS:SENS-111 was well tolerated with mild to moderate events. No sedation was reported. A maximal tolerated dose was not reached. Dose-proportional increases in concentrations were seen up to 200 mg and more than dose-proportional thereafter, with mean half-life between 24 and 56 h. The caloric test induced mild but measurable vertigo and nystagmus with large intra/inter-individual variation for all parameters. SENS-111 did not significantly impact nystagmus but significantly improved latency of vertigo appearance/disappearance, duration and European Evaluation of Vertigo questionnaire parameters vs. baseline. A two-compartment model with first-order absorption, distribution and elimination best fit the data. PK/PD indirect modelling applied to vertigo duration and latency of appearance indicated maximum activity between 100 and 500 ng ml-1 plasma concentrations, corresponding to 100 and 200 mg day-1 , which are appropriate for clinical efficacy evaluations in vestibular diseases.CONCLUSIONS:SENS-111 is a well-tolerated first-in-class H4 receptor antagonist with acceptable PK for oral daily dosing. PK/PD modelling determined plasma concentrations and doses for efficacy studies in patients with vertigo symptoms.
Databáze: OpenAIRE
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