Relative equivalence of CNS safety (FOB) assessment outcomes in male and female Wistar-Han and Sprague-Dawley rats.

In 2006 the National Toxicology Program (NTP) of the FDA shifted to the preferred use of Wistar-Han rats from the more commonly used Sprague-Dawley (SD) strain - and industry followed. While European laboratories preferred the Wistar-Han line, there was a paucity of relevant historical control data in many US research institutions for the new "industry standard" rat strain. In 2010 the NTP reversed its decision and shifted back to SD rats because of reproductive issues with the Wistar strain. For post hoc comparative analyses, we report minimal practical differences in Functional Observational Battery (FOB) data from a large sample of male and female Wistar-Han and SD rats. In summarizing data from the preclinical safety evaluations of the CNS effects of new drugs using the FOB, it is crucial to understand the value of not only how the functional expression of drug effects in the rat are predictive of the human response, but also how and why they differ. What we can predict from the behavioral and physiological response of the designated test system to drug administration is the foundation of "generalizability" to the human's response. Here, we conclude that the use of either SD or WH rat strains in standard CNS safety studies provide equivalent supportive data for CNS safety assessment required for IND approval under the harmonized guidelines.

A predictive index of biomarkers for ictogenesis from tier I safety pharmacology testing that may warrant tier II EEG studies.

Three significant contributions to the field of safety pharmacology were recently published detailing the use of electroencephalography (EEG) by telemetry in a critical role in the successful evaluation of a compound during drug development (1] Authier, Delatte, Kallman, Stevens & Markgraf; JPTM 2016; 81:274-285; 2] Accardi, Pugsley, Forster, Troncy, Huang & Authier; JPTM; 81: 47-59; 3] Bassett, Troncy, Pouliot, Paquette, Ascaha, & Authier; JPTM 2016; 70: 230-240). These authors present a convincing case for monitoring neocortical biopotential waveforms (EEG, ECoG, etc) during preclinical toxicology studies as an opportunity for early identification of a central nervous system (CNS) risk during Investigational New Drug (IND) Enabling Studies. This review is about "ictogenesis" not "epileptogenesis". It is intended to characterize overt behavioral and physiological changes suggestive of drug-induced neurotoxicity/ictogenesis in experimental animals during Tier 1 safety pharmacology testing, prior to first dose administration in man. It is the presence of these predictive or comorbid biomarkers expressed during the requisite conduct of daily clinical or cage side observations, and in early ICH S7A Tier I CNS, pulmonary and cardiovascular safety study designs that should initiate an early conversation regarding Tier II inclusion of EEG monitoring. We conclude that there is no single definitive clinical marker for seizure liability but plasma exposures might add to set proper safety margins when clinical convulsions are observed. Even the observation of a study-related full tonic-clonic convulsion does not establish solid ground to require the financial and temporal investment of a full EEG study under the current regulatory standards. PREFATORY NOTE: For purposes of this review, we have adopted the FDA term "sponsor" as it refers to any person who takes the responsibility for and initiates a nonclinical investigations of new molecular entities; FDA uses the term "sponsor" primarily in relation to investigational new drug application submissions.