Dataset Information

Safety, tolerability, pharmacokinetics and pharmacokinetic-pharmacodynamic modelling of the novel H₄ 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.

SUBMITTER: Venail F

PROVIDER: S-EPMC6255991 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Dataset Information

Safety, tolerability, pharmacokinetics and pharmacokinetic-pharmacodynamic modelling of the novel H₄ receptor inhibitor SENS-111 using a modified caloric test in healthy subjects.

Aim

Methods

Results

Conclusions

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Safety, tolerability, pharmacokinetics and pharmacokinetic-pharmacodynamic modelling of the novel H₄ receptor inhibitor SENS-111 using a modified caloric test in healthy subjects.