Title: Novel test strategies for in vitro seizure liability assessment.

Authors: Tukker, Anke M; Westerink, Remco H S

Published In Expert Opin Drug Metab Toxicol, (2021 Aug)

Abstract: INTRODUCTION: The increasing incidence of mental illnesses and neurodegenerative diseases results in a high demand for drugs targeting the central nervous system (CNS). These drugs easily reach the CNS, have a high affinity for CNS targets, and are prone to cause seizures as an adverse drug reaction. Current seizure liability assessment heavily depends on in vivo or ex vivo animal models and is therefore ethically debated, labor intensive, expensive, and not always predictive for human risk. AREAS COVERED: The demand for CNS drugs urges the development of alternative safety assessment strategies. Yet, the complexity of the CNS hampers reliable detection of compound-induced seizures. This review provides an overview of the requirements of in vitro seizure liability assays and highlights recent advances, including micro-electrode array (MEA) recordings using rodent and human cell models. EXPERT OPINION: Successful and cost-effective replacement of in vivo and ex vivo models for seizure liability screening can reduce animal use for drug development, while increasing the predictive value of the assays, particularly if human cell models are used. However, these novel test strategies require further validation and standardization as well as additional refinements to better mimic the human in vivo situation and increase their predictive value.

PubMed ID: 33595380

MeSH Terms: Animals; Central Nervous System Agents/administration & dosage; Central Nervous System Agents/adverse effects*; Cost-Benefit Analysis; Drug Development/methods; Humans; Microelectrodes; Models, Biological*; Predictive Value of Tests; Seizures/chemically induced*; Seizures/diagnosis