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Keywords:

  • convulsions;
  • mechanistic studies;
  • strategy

Abstract

Preclinical ResearchPreclinical Development Toxicology, Formulation Drug Delivery, Pharmacokinetics

The occurrence of convulsions in nonclinical safety studies during development of a new drug often complicates further development of the compound. Based on experiences with a previous development project at H. Lundbeck A/S, where convulsions were noted in animals, a structured approach to investigate possible mechanisms behind the convulsions is suggested. Because it is typically difficult to determine the exact reason for convulsions, it is important to focus on the assessment of possible human risk rather than finding the exact mechanism behind the convulsions. The suggested investigations include the following: calculation of safety margin and assessment of human risk, evaluation of data already captured in performed studies such as clinical chemistry data, description of clinical signs, batches of compound used, expert advice on activities that could enable further development of the compound, investigation of extended in vitro receptor profiles of parent compound and major metabolites, extended histopathology on brain sections, seizure threshold tests of parent compound and major metabolites (in vivo/in vitro), evaluation of electroencephalograms, and finally contact with authorities to discuss a plan for continued clinical development.