title: A retrospective evaluation of species-specific sensitivity for neurological signs in toxicological studies: Is the dog more sensitive than the non-human primate?
abstract: Selection of the appropriate non-rodent species in preclinical programs is crucial for good translatability and human safety. There is no data available in the literature which provides exact comparison of dog and non-human primate (NHP) sensitivity regarding neurological signs in toxicological studies. We performed a retrospective analysis of 174 toxicity studies with 15 neuroscience substances. Neurological signs in dogs and NHPs were evaluated in correlation to exposure data. Overall incidence of substance induced convulsions was similar in both species and no gender differences were observed. The reported liability of beagles to spontaneous convulsions was not confirmed in our studies. The symptom tremor showed the best inter-species translatability. The current toxicological study design does not include exposure assessment at the time-point of neurological signs, therefore, we propose to include additional toxicokinetic samples. Our analysis revealed factors including housing, handling, and behavior, which prevents direct species comparison. In addition only one non-rodent species is routinely tested in development programs, therefore data for both species is rare. We however, had sufficient data which enabled comparison for one compound. In the spirit of 3Rs further examples should be evaluated.
authors.affiliation: AbbVie Deutschland GmbH & Co. KG, Ludwigshafen, Germany.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Backes
authors.affiliation: AbbVie Deutschland GmbH & Co. KG, Ludwigshafen, Germany.
authors.forename: Helga
authors.initials: H
authors.lastname: Lorenz
authors.affiliation: AbbVie Deutschland GmbH & Co. KG, Ludwigshafen, Germany.
authors.forename: Loic
authors.initials: L
authors.lastname: Laplanche
authors.affiliation: AbbVie Inc., Lake County, Illinois, USA.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Hudzik
authors.affiliation: Institute of Pharmacology, Toxicology and Pharmacy, Ludwig-Maximilians-University (LMU), Munich, Germany.
authors.forename: Heidrun
authors.initials: H
authors.lastname: Potschka
authors.affiliation: AbbVie Deutschland GmbH & Co. KG, Ludwigshafen, Germany. Electronic address: katja.hempel@abbvie.com.
authors.forename: Katja
authors.initials: K
authors.lastname: Hempel
mesh_terms: D000818:Animals; D004285:Dogs; D005260:Female; D008297:Male; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D011323:Primates; D012189:Retrospective Studies; D012640:Seizures / Q000139:chemically induced / Q000473:pathology; D013045:Species Specificity; D013261:Sterols / Q000097:blood / Q000633:toxicity; D018675:Toxicity Tests; D014202:Tremor / Q000139:chemically induced / Q000473:pathology
chemical_list: D013261:Sterols; C016315:compound D(k)
keywords: Non-rodent; Species selection; Toxicology