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

Abstract : 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.
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https://hal.umontpellier.fr/hal-02315424
Contributeur : Anthony Herrada <>
Soumis le : lundi 14 octobre 2019 - 14:38:00
Dernière modification le : vendredi 15 mai 2020 - 12:22:05

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Frederic Venail, Pierre Attali, Eric Wersinger, Roberto Gomeni, Sonia Poli, et al.. Safety, tolerability, pharmacokinetics and pharmacokinetic-pharmacodynamic modelling of the novel H 4 receptor inhibitor SENS-111 using a modified caloric test in healthy subjects. British Journal of Clinical Pharmacology, Wiley, 2018, 84 (12), pp.2836-2848. ⟨10.1111/bcp.13744⟩. ⟨hal-02315424⟩

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