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

Br J Clin Pharmacol. 2018 Dec;84(12):2836-2848. doi: 10.1111/bcp.13744. Epub 2018 Oct 1.

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.

Keywords: nystagmus; pharmacokinetics/pharmacodynamics; type-4 histamine receptor; vertigo; vestibular disorders.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Azetidines / adverse effects*
  • Azetidines / pharmacokinetics
  • Azetidines / pharmacology
  • Caloric Tests*
  • Double-Blind Method
  • Healthy Volunteers
  • Histamine Antagonists / adverse effects*
  • Histamine Antagonists / pharmacokinetics
  • Histamine Antagonists / pharmacology
  • Humans
  • Male
  • Middle Aged
  • Models, Biological
  • Pyrimidines / adverse effects*
  • Pyrimidines / pharmacokinetics
  • Pyrimidines / pharmacology
  • Receptors, Histamine H4 / antagonists & inhibitors*
  • Vertigo / drug therapy
  • Young Adult

Substances

  • Azetidines
  • Histamine Antagonists
  • Pyrimidines
  • Receptors, Histamine H4
  • seliforant