Effect of the novel histamine H4 receptor antagonist SENS-111 on spontaneous nystagmus in a rat model of acute unilateral vestibular loss

Abstract

Background and Purpose: Histamine H4 receptors are expressed in the peripheral vestibular system, and their selective inhibition improves vertigo symptoms in rats with unilateral vestibular lesions. The effects of SENS-111, a selective oral H4 receptor antagonist with high affinity to both animal and human receptors, on vertigo symptoms was evaluated in a translational in vivo model of unilateral vestibular loss. Experimental Approach: Pharmacokinetics of SENS-111 in rats was determined to aid dose selection for efficacy testing. Vestibular lesions were induced in rats by unilateral transtympanic injection of kainic acid. The effect of SENS-111 (10 or 20 mg·kg−1) on spontaneous nystagmus was evaluated compared with placebo vehicle using video-nystagmography, and the effective dose was compared with those of similar drugs used clinically, as single agents or combined with SENS-111. Key Results: Doses were selected for plasma exposure were consistent with published phase 1 results from healthy volunteers. SENS-111 of 10 mg·kg−1 gave a 21–22% reduction in nystagmus at 1 hr post-administration, whereas a loss of efficacy was seen with 20 mg·kg−1. Compared with SENS-111, meclizine and methylprednisolone had minimal effects on nystagmus as single agents, and meclizine abolished the effect of SENS-111 when combined with SENS-111. All evaluated drugs were well tolerated. Conclusions and Implications: The exposure-efficacy relationship for improved spontaneous nystagmus seen with SENS-111 in this in vivo model is consistent with phase 1 clinical results and provides preclinical support for pharmacokinetic/pharmacodynamic modelling and selection of effective clinical drug concentrations. Linked Articles: This article is part of a themed section on New Uses for 21st Century. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.3/issuetoc.