STRATEGY FOR AND EXPERIENCE WITH NEUROTOXICITY TESTING OF NEW PHARMACEUTICALS

In response to present and anticipated regulatory needs for routine sc reening of pharmaceuticals for assessment of their neurotoxic potentia l, a primary tier screen for rodents, consisting of a functional obser vational battery (FOB) and an automated test of motor activity, has be en developed at Searle. Additionally, an FOB for dogs currently is bei ng developed. The rodent FOB assess such functions as home cage and op en field activity, stimulus reactivity, and neuromuscular function. Th e dog FOB emphasizes evaluation of gait, postural reactions, and refle x function. The strategy taken has been to incorporate the primary rod ent tier screen into repeated dose preclinical studies. Positive findi ngs 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 trig ger secondary tier testing are discussed.