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Primate testing in Europe

Replacing primates

Advanced scientific techniques to replace the use of primates in regulatory and commercial testing

Developments in science and technology have provided new techniques to replace animals, which provide data relevant to humans. An intelligent, cross-disciplinary approach is needed, which draws upon the very best in technology.

There is a clear and urgent imperative: by the time primates and dogs have been selected for testing, other animals have already suffered and died for the same products. Replacement of primates is an achievable goal.
Microdosing and Acceleratory Mass Spectrometry (AMS): A ‘microdose’ is defined as less than one hundredth of the proposed pharmacological dose but never exceeding 100µg199. Drug levels from microdosing can be measured in any biological sample such as plasma or urine to determine ADME (absorption, distribution, metabolism and secretion) and pharmacokinetic characteristics of a drug. Analysis uses an Accelerator Mass Spectrometer (AMS)200, which can count individual atoms and has the ability to detect a liquid compound even after just one litre of it has been diluted in the ocean201. A recent EU study over a period of 31 months demonstrated the value of microdosing in drug development202, comparing microdosing data to animal tests. For example, rat data for the compound phenobarbital over-predicted the clearance of the drug in humans, and under-predicted the compound’s half-life (measure of drug metabolism). The microdosing data proved more accurate and was 80% predictive of ADME in people203.

This demonstrates that microdosing and AMS is significantly more accurate than primate, dog and rodent models. Microdosing could accelerate drug development. Preclinical studies can take 18 months and cost $3-5 million. Microdosing can reduce the time to 4 to 6 months and the cost to $0.35m per new molecule204. Other options for replacement through microdosing strategies include PET (positron emission tomography)205 and human volunteers. It has been concluded that microdosing, could improve selection of new compounds and reduce failures206.

QSARs (Quantitative Structure Activity Relationships) computer modelling; correlates a compounds’ structure and properties with its activity. QSAR is used in drug design and environmental risk assessment207, it can play a significant role in assessing toxicity and pharmacokinetics and can be used to determine target organ or system doses208.

Derek for windows (DfW) is an expert knowledge base system (a computer program that applies rules), which predicts a chemical’s toxicity from its molecular structure209 by applying QSARs and other knowledge rules 209.

Human cell lines: An EU project, ‘vitrocellomics’ aimed to provide “…new, efficient in vitro prevalidation models, which will significantly reduce the use of animal experimentation for prediction of human drug metabolism by 60-80%”210, 211. Specialised cell cultures, such as hepatocytes (liver cells), allow researchers to conduct multiple studies on multiple days using hepatocytes from a single donor to assess intra-assay variability and to study multiple endpoints (i.e. transport and metabolism)212. A variety of in vitro systems have been under development, derived mainly from the liver, kidney and brain 208.

Human tissue use: Pharmaceutical companies use liver tissue to provide biological data and safety test compounds; “animal drug metabolism is very different to human and it may be more appropriate to use human liver tissue early in a new drugs life to establish metabolites that may be toxic to humans”213.
Scaffolds and 3-Dimensional (3D) cultures can be formed in different tissue, and used as models for pharmaceutical and drug discovery. The scaffold can be made from synthetic or natural materials, with differing scientific advantages214. Tissue can be constructed to recreate whole body systems, such as the human artificial immune system, which assesses a substance’s interaction with the immune system215.

High throughput screening: This technique, involving robotics and sophisticated control software, rapidly analyses compounds for drug discovery, often to generate starting points for drug development216.

Biochips: These show the effect on different cells in the body and how toxicity is altered when the compound is broken down (metabolized) in the human body. They provide “comprehensive toxicity data very quickly and cheaply” and can provide data on the toxicity on different human organs217.

Toxicogenomics: This seeks to translate data about genetic variation and gene expression into an understanding of the biological systems in organisms, including humans, and the effects of changes in the systems on the organism’s health. Toxicogenomics may improve understanding in processes such as reproductive toxicity and nongenotoxic carcinogenesis, usually carried out in long-term animal studies, and “help treat people at the greatest risk of diseases caused by environmental pollutants or toxicants”218. Antidote Europe has developed a novel approach to toxicogenomics by using miniaturized DNA chips, in combination with sequential exposure of two different cell types, approximating what would occur in a whole body and call the approach ‘Scientific Toxicology Program’ (STP)219.

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