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Office-led project

Refining MTD studies

At a glance

Completed
Current contacts

R

  • Refinement

Contents

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Overview

Maximum tolerated dose (MTD) studies are used to set the doses for short and long-term toxicology studies in animals and to determine safe starting doses for first-in-man clinical trials. The data from these studies can be used to avoid conventional single dose toxicology studies.

We have provided evidence to refine MTD studies focusing on body weight loss. Body weight loss is often used as a surrogate measure of animal welfare and as an objective clinical endpoint to decide when to terminate studies. Based on an analysis of 151 compounds from 13 companies we have published recommendations for maximum body weight loss limits of 10% in the rat and dog and 6% in non-human primates [1] - lower limits than current practice for MTD studies.

 

Table: Improving animal welfare: refining maximum % body weight loss in MTD studies
  Rat Dog Non-human primate
Typical >20 >16 >10
Refined 10 10 6

 

Body Weight Loss (BWL) decision tree for use with rat and dog only to determine the maximum-tolerated-dose in short-term toxicity studies
Body weight loss decision tree for rats and dogs

Publications

  1. Chapman K et al. (2013). A Global Pharmaceutical Company Initiative: An Evidence-Based Approach to Define the Upper Limit of Body Weight Loss in Short Term Toxicity Studies. Regulatory Toxicology and Pharmacology 67(1):27-38. doi: 10.1016/j.yrtph.2013.04.003
  2. Factsheet: Recommendations for upper bodyweight loss limits in short-term toxicity studies. May 2013.
  3. NC3Rs/LASA Guidance on dose level selection for regulatory general toxicology studies for pharmaceuticals. 2009.