Strategy for and Experience with Neurotoxicity Testing of New Pharmaceuticals

Abstract

In response to present and anticipated regulatory needs for routine screening of pharmaceuticals for assessment of their neurotoxic potential, a primary tier screen for rodents, consisting of a functional observational battery (FOB) and an automated test of motor activity, has been developed at Searle. Additionally, an FOB for dogs currently is being developed. The rodent FOB assess such functions as home cage and open field activity, stimulus reactivity, and neuromuscular function. The dog FOB emphasizes evaluation of gait, postural reactions, and reflex function. The strategy taken has been to incorporate the primary rodent tier screen into repeated dose preclinical studies. Positive findings would trigger a secondary tier of testing, which would involve the use of more complex and integrated tests of neurobehavioral function. The methodologies for both rodent and nonrodent primary tier screens, validation study results, and the scientific criteria that would trigger secondary tier testing are discussed.