Assessing the predictive value of the rodent neurofunctional assessment for commonly reported adverse events in phase I clinical trials

Autor: Andy N. Mead, Pierre Jordaan, Kathryn Chapman, Will S. Redfern, Alessandra Giarola, Jean-Pierre Valentin, Samuel J. Jackson, Lorna Ewart, Philip Jarvis, Hugo M. Vargas, Martin Traebert, Hamid R. Amouzadeh
Rok vydání: 2016
Předmět:
0301 basic medicine
Translation
medicine.medical_specialty
Drug-Related Side Effects and Adverse Reactions
Nausea
Concordance
Predictive value
Context (language use)
Functional observational battery
Toxicology
Risk Assessment
030226 pharmacology & pharmacy
Mice
03 medical and health sciences
0302 clinical medicine
Species Specificity
Central Nervous System Diseases
Toxicity Tests
Methods
medicine
Animals
Humans
Intensive care medicine
Adverse effect
Behavior
Animal
Clinical Trials
Phase I as Topic
Dose-Response Relationship
Drug
business.industry
Reproducibility of Results
Neurobehavioural assessment
General Medicine
Rats
Clinical trial
030104 developmental biology
Central nervous system
Adverse events
First-in-human
Anesthesia
Observational study
medicine.symptom
business
Risk assessment
Somnolence
Zdroj: Regulatory Toxicology and Pharmacology. 80:348-357
ISSN: 0273-2300
DOI: 10.1016/j.yrtph.2016.05.002
Popis: Central Nervous System (CNS)-related safety concerns are major contributors to delays and failure during the development of new candidate drugs (CDs). CNS-related safety data on 141 small molecule CDs from five pharmaceutical companies were analyzed to identify the concordance between rodent multi-parameter neurofunctional assessments (Functional Observational Battery: FOB, or Irwin test: IT) and the five most common adverse events (AEs) in Phase I clinical trials, namely headache, nausea, dizziness, fatigue/somnolence and pain. In the context of this analysis, the FOB/IT did not predict the occurrence of these particular AEs in man. For AEs such as headache, nausea, dizziness and pain the results are perhaps unsurprising, as the FOB/IT were not originally designed to predict these AEs. More unexpected was that the FOB/IT are not adequate for predicting ‘somnolence/fatigue’ nonclinically. In drug development, these five most prevalent AEs are rarely responsible for delaying or stopping further progression of CDs. More serious AEs that might stop CD development occurred at too low an incidence rate in our clinical dataset to enable translational analysis.
Databáze: OpenAIRE
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