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

摘要

Aim A Phase 1 study was performed to evaluate safety, pharmacokinetics (PK) and pharmacodynamics (PD) of the selective histamine H 4 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 H 4 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.