Background and Purpose Histamine H 4 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 H 4 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