The maximum-tolerated dose of a drug candidate can be determined in short-term toxicity studies without exceeding a bodyweight loss of 10 per cent in rats and dogs, according to a review by 15 pharmaceutical companies and contract research organisations published in Regulatory Toxicology and Pharmacology.
Led by the UK's National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs) and AstraZeneca, data from short-term toxicity studies of up to seven days in duration was collected from a multinational industry collaboration. The evidence sets out a new upper limit of bodyweight loss to be used as a primary endpoint for selecting the highest dose of a drug that can be tolerated in animals to reduce the likelihood of major adverse effects.
The maximum-tolerated dose is usually determined by parameters such as bodyweight loss, clinical signs and a change in food consumption. However, such assessments are often subjective with little regulatory or cross-industry agreement on how the maximum-tolerated dose should be defined. Bodyweight loss is one of the few objective measurements used in short-term toxicity studies. It is used as a measure of animal welfare, with the greater the weight loss the greater the potential for suffering.
To date there has been no evidence-based guidance on the upper limit for bodyweight loss. In this NC3Rs-industry collaboration, data sharing on 151 compounds has shown the upper limit for bodyweight loss ranges from 15 to 25 per cent in practice. Detailed analysis of the data however has shown that there is little scientific value in exceeding bodyweight loss limits of 10 per cent in rats and dogs to determine the maximum-tolerated dose for future dosing decisions.
Bodyweight loss above these limits has been found to almost always be associated with additional clinical signs.
Along with the new recommended limits, an alert system has been developed to determine when the maximum-tolerated dose has been reached. While bodyweight loss is used here as an objective measurement, the presence of other clinical signs is also incorporated to add value to this practical advice. These standardised assessment criteria will minimise the adverse effects experienced by thousands of animals used in pharmaceutical development each year.
Study author Dr Kathryn Chapman, Head of Innovation and Translation, NC3Rs, said: "Acting as an honest broker in this way has proven successful to identify an objective methodology to minimise animal suffering in short-term toxicity studies. Defining the maximum-tolerated dose is crucially important for this in addition to making it easier to select an appropriate dose for future studies."
Co-author Dr Sally Robinson, AstraZeneca, said: "We have shared data across global pharmaceutical companies and developed an evidence base to support significant refinement in short-term toxicity studies where high doses of potential new medicines are given. The outcome from this novel approach can potentially be applied more broadly than the pharmaceutical industry delivering even greater animal welfare benefits in short-term toxicity studies which often have the highest severity limits."
Co-author Dr Vicente Nogués, Head of Operations for Preclinical Safety, Novartis Institute for Biomedical Research, said: "Novartis has gained confidence that the conclusions of this investigation, based on the analysis of a considerable historical database throughout the pharmaceutical industry, will help to improve overall decision making during animal study conduct along the 3Rs; this without harming the ultimate objective of the preclinical studies."
Maximum-tolerated dose studies are important from both a scientific and ethical perspective. They are used to make decisions on the progression of potential candidate drugs across a range of therapeutic areas. They also set the dose level for subsequent studies that allow for regulatory approval. This approach to re-assessing bodyweight loss has the potential to be translated to other research areas including pharmacology and efficacy studies and short-term toxicity studies with chemicals.
Notes for Editors:
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Chapman K, Sewell F, Allais L, Delongeas J-L, Donald E, Festag M, Kervyn S, Ockert D, Nogués V, Palmer H, Popovic M, Roosen W, Schoenmakers A, Somers K, Start C, Stei P, Robinson, S (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. http://dx.doi.org/10.1016/j.yrtph.2013.04.003
For the list of 10 pharmaceutical companies and 5 CROs participating in the collaboration, please see the original paper.