Toxicokinetic analysis identifies the level of drug exposure which elicits an adverse event in animals. Most short and long-term toxicity studies include ‘main study animals’ which are used to determine potential adverse effects, plus ‘satellite animals’ for toxicokinetics. Direct biological comparison of exposure and adverse events in the same animal is limited by the volume of blood required for analysis – typically around 200µl per time point.
For small molecules, bioanalytical methods exist that allow drugs to be measured in blood samples of less than 50µl per time point. This provides the opportunity to take microsamples of blood from the main study group without the need for satellite animals, giving scientific as well as 3Rs benefits. Removing the need for specific groups of rodents for the sole purpose of toxicokinetics represents the single biggest opportunity to reduce the use of animals in regulatory toxicology studies – providing up to a 55% reduction for some studies.
The potential level of reduction from the use of microsampling: comparison of conventional and microsampling study designs using rats and mice. The number of male and female main study animals and satellite animals are shown per dose group and typical numbers assume three dose groups plus control. The reduction in animal use ranges from 23% to 55% depending on the number of satellite animals used (which differs between companies and studies).
Sparrow S., et al (2011). Opportunities to minimise animal use in pharmaceutical regulatory general toxicology: A cross company review. Regulatory Toxicology and Pharmacology 61(2): 222-229. doi:10.1016/j.yrtph.2011.08.001
Chapman K., et al (2014). Overcoming the barriers to the uptake of nonclinical microsampling in regulatory safety studies. Drug Discovery Today 19(5): 528-32. doi:10.1016/j.drudis.2014.01.002