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Drug‐Induced Convulsions in Nonclinical Safety Studies: Implication for Clinical Development

Drug‐Induced Convulsions in Nonclinical Safety Studies: Implication for Clinical Development Preclinical Research Preclinical 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. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Drug Development Research Wiley

Drug‐Induced Convulsions in Nonclinical Safety Studies: Implication for Clinical Development

Elander, Mikael
Drug Development Research , Volume 74 (3) – May 1, 2013
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References (44)

Publisher
Wiley
Copyright
Copyright © 2013 Wiley Periodicals, Inc., A Wiley Company
ISSN
0272-4391
eISSN
1098-2299
DOI
10.1002/ddr.21061
Publisher site
See Article on Publisher Site

Abstract

Preclinical Research Preclinical 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.

Journal

Drug Development Research – Wiley

Published: May 1, 2013

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