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Primate testing in Europe

Drug development and safety testing using animals

The fundamental flaw of using animal test results to establish safety for humans is that of species differences. All species react differently to drugs and chemicals, because of the differences in genetics and biology, and many of these differences are well known. In addition, biochemical changes in the animals’ bodies as a result of the stress of being used in the laboratory can also affect test outcomes. The development and use of advanced non-animal techniques therefore offers improved scientific method, and improved results, more relevant to humans.

The way a drug travels through the body – the rate and route by which it breaks down and moves through the body, before being excreted – is crucial. This is referred to as the drug’s ADME (absorption, distribution, metabolism and excretion). Our genes, and other factors, influence the ADME of a drug. For this reason, despite the similarities between humans and the other primates, the small but key genetic differences between ourselves and non-human primates are hugely important in drug development and testing.

A review of animal use in drug development concluded “Some species of experimental animals have such unique mechanisms of developing toxicity that extrapolation of such toxicity assessments to the human situation would be fraudulent”[9]. A study of data from the rat, dog, monkey and human reported that “the monkey overall tended to be the most similar to human, with only 32 of the 103 compounds (31%) in a different clearance category compared with humans”[10]. Therefore the primate model is different nearly a third of the time.

Researchers have recently commented, “experimental animals sometimes show significant species differences in the oral BA [when a substance is in a form that allows it to be metabolized] of drugs that might lead to the erroneous prediction of the BA in humans”[11].

Others have commented: “The many intrinsic differences in the ADME processes between animals and humans make extrapolation of animal data very difficult”, furthermore, “in the past 30 years, pharmacokineticists have failed to find an animal species in which the ADME processes of drugs are consistently the same as those in humans. In fact, it can be presumed that such an animal species will never be found”[12].

Use of data from primates has been criticised: “despite the similarities in monkey and human absorption kinetics, marked differences are found in oral bioavailability (lower in monkey) as well as in total and non-renal plasma clearances (both higher in monkey). ... caution should be exercised in extrapolating data obtained in monkeys as it may not predict that in humans“[13].

Differences between humans and the cynomolgus macaque (macaca fascicularis) used at HLS in drug and vaccine testing and development are relevant to this discussion:

  • Certain genes (cytochrome) create enzymes which are important in the metabolism of drugs yet there are differences between humans and the cynomolgus monkey. “Gene and protein expression of CYP2C76 was confirmed in the liver of cynomolgus and rhesus monkeys but not in humans or the great apes”14. This gene is “a major CYP2C in the monkey liver” and “CYP2C76 contributes to overall drug-metabolising activity in the monkey liver”[14]. A later paper by the same author concluded “Cynomolgus monkey CYP2C76 does not have a corresponding ortholog in humans, and it is partly responsible for differences in drug metabolism between monkeys and humans”[15] (our emphasis).
  • Researchers investigated the way that genes affect the metabolism of drugs. It was concluded that the mechanisms involved “differ between humans and cynomolgus monkeys”[16], in addition “there is little information available on the induction of CYP enzymes in cynomolgus monkey hepatocytes”[16].
    In conclusion, the macaque model being used is not fully understood and macaques have drug-metabolising enzymes that are absent in humans.
  • It has been obvious for some time that there is generally no evolutionary basis behind the particular-metabolizing ability of a particular species. Indeed, among primates, zoologically closely related species exhibit markedly different patterns of metabolism”[17].
  • A detailed investigation of safety testing by the Toxicology Working Group of the UK’s House of Lords Select Committee on Animals in Scientific Procedures concluded: “the formulaic use of two species in safety testing is not a scientifically justifiable practice, but rather an acknowledgement of the problem of species differences in extrapolating the results of animal tests to predict effects in humans”, and, “the reliability and relevance of all existing animal tests should be reviewed as a matter of urgency”[18].
  • Drs Palfreyman, Charles and Blander in ‘Drug Discovery World’ observed: “One of the major challenges facing the drug discovery community is the poor predictability of animal-based strategies . . . many drugs have failed in later stages of development because the animal data were poor predictors of efficacy in the human subject . . . . One of the overriding interests of the pharmaceutical and biotechnologies industry is to create alternative development strategies that are less reliant on poor animal predictor models of human disease . . .”[19].

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