Case Studies in Identifying and Understanding Seizure Liability in Drug Development

Drug-induced seizures are among the most frequent safety concerns for neuroactive drug candidates. Currently, no guidelines are defined for interrogating and mitigating seizure liability. Because of the risks to patient safety during clinical trials, improved nonclinical characterization of seizure liability is an area of intense interest among drug developers and regulators. During the 2022 annual meeting of the American College of Toxicology (ACT), a continuing education course titled "Identifying and Understanding Seizure Liability in Drug Development" addressed challenges in this field. The course (and now this paper) used a series of detailed nonclinical case studies based on the authors' experiences to illustrate core principles and a flexible menu of methods to evaluate potential seizure liability. Key points to consider include lists of (1) procedures for detecting seizures and defining their mechanisms when performing pivotal and/or investigational toxicity studies; (2) constellations of common neurological findings (functional and structural) that indicate potential seizure liability, and in particular (3) event patterns that warrant an electroencephalographic (EEG) study; and (4) major principles for mitigating seizure liability during clinical trials. Taken together, this approach provides a logical workflow by which nonclinical testing of drug-related seizures may be used to best protect patient safety.