Cetirizine in horses: Pharmacokinetics and pharmacodynamics following repeated oral administration Lena Olse ´n a, * , Ulf Bondesson b,c , Hans Brostro ¨m d , Hans Tja ¨lve a , Carina Ingvast-Larsson a a Division of Pathology, Pharmacology and Toxicology, Department of Biomedical Sciences and Veterinary Public Health, Swedish University of Agricultural Sciences, SE-750 07 Uppsala, Sweden b Division of Analytical Pharmaceutical Chemistry, Biomedical Center, Uppsala University, SE-751 23 Uppsala, Sweden c Department of Chemistry, National Veterinary Institute, SE-751 89 Uppsala, Sweden d Division of Medicine and Surgery, Department of Clinical Sciences, Swedish University of Agricultural Sciences, SE-750 07 Uppsala, Sweden Accepted 28 March 2007 Abstract The pharmacokinetics of the histamine H 1 -antagonist cetirizine and its effect on histamine-induced cutaneous wheal formation were studied in six healthy horses following repeated oral administration. After three consecutive administrations of cetirizine (0.2 mg/kg body weight, bw) every 12 h, the trough plasma concentration of cetirizine was 16 ± 4 ng/mL (mean ± SD) and the wheal formation was inhibited by 45 ± 23%. After four additional administrations of cetirizine (0.4 mg/kg bw) every 12 h, the trough plasma concentration was 48 ± 15 ng/mL and the wheal formation was inhibited by 68 ± 11%. The terminal half-life was about 5.8 h. A pharmacokinetic/ pharmacodynamic link model showed that the maximal inhibition of wheal formation was about 95% and the EC 50 about 18 ng/mL. It is concluded that cetirizine in doses of 0.2–0.4 mg/kg bw administered at 12 h intervals exhibits favourable pharmacokinetic and phar- macodynamic properties without causing visible side effects, and the drug may therefore be a useful antihistamine in equine medicine. Ó 2007 Elsevier Ltd. All rights reserved. Keywords: Horse; Antihistamine; Cetirizine; PK/PD link model Introduction Histamine is an important chemical mediator, which is involved in the aetiology of various hypersensitivity mani- festations via interactions with histamine H 1 -receptors. Specific IgE antibodies attached to mast cells cross-bind antigens and induce release of histamine and other immu- nological mediators. This results in type 1 allergic reac- tions, which are characterised by dilatation of vascular smooth muscle, increased permeability of capillary endo- thelium and contraction of bronchial smooth muscle. In equine therapy, histamine H 1 -antagonists (antihista- mines) such as tripelennamine, promethazine and chlor- phentamine have been used in conditions in which histamine is a critical mediator, such as allergic reactions to venoms and other antigens and drug-related immuno- logical reactions, including anaphylactic shock (Morrow et al., 1986; Adams, 1995; Rosenkrantz, 1995; Foster et al., 1998). Antihistamines may also be useful to treat the syndrome called ‘‘sweet itch’’, ‘‘summer eczema’’ or ‘‘allergic urticaria’’. This is a worldwide chronic seasonally recurrent pruritic allergic skin disease in horses hypersensi- tive to antigens in the saliva of biting flies, in particular midges of the genus Culicoides, and sometimes also black flies from the genus Simulium (Baker and Quinn, 1978; Braverman et al., 1983; Quinn et al., 1983; Brostro ¨m et al., 1987; Greiner et al., 1988, 1990; Hallorsdottir et al., 1989; Fadok and Greiner, 1990; Anderson et al., 1991, 1993; Marti et al., 1999; Mullens et al., 2005; Baselgia et al., 2006). It is known that IgE plays a role in the pathogenesis of this syndrome (Matthews et al., 1983; Van der Haegen et al., 2001; Wilson et al., 2001, 2006; Ru ¨ fenacht et al., 1090-0233/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.tvjl.2007.03.026 * Corresponding author. Tel.: +46 18 67 31 76; fax: +46 18 50 41 44. E-mail address: Lena.Olsen@bvf.slu.se (L. Olse ´n). www.elsevier.com/locate/tvjl Available online at www.sciencedirect.com The Veterinary Journal 177 (2008) 242–249 The Veterinary Journal