Cynomolgus monkeys are resistant to drug induced liver injury caused by paracetamol
by Dr Gerry Kenna
Prior to their registration for use in humans, all new drugs are subjected to a large battery of safety studies. These include an extensive series of investigations in experimental animals, which are undertaken in compliance with well-established regulatory guidelines, and careful safety monitoring of all human clinical trials. Although these approaches are effective in ensuring that new drug candidates do not cause frequent and clinically concerning adverse reactions (ADRs) during clinical trials, many hundreds of widely prescribed drugs cause infrequent human ADRs which occur at incidences below one in several hundred treated patients. Infrequent human ADRs often affect the liver and/or skin, although other systems may also be affected. They can result in serious illness, or even fatality, and are a leading cause of serious illness requiring hospitalisation, restrictive drug labelling/ drug usage, and/or withdrawal from use of otherwise efficacious and valuable therapies. Consequently it is important to develop new drug safety testing strategies, which can underpin the selection and development of safer drugs in the future.
One possible explanation for the inability of safety studies undertaken in animals to identify compounds which may cause infrequent human ADRs might be that they use animal species used in the studies are too dissimilar biologically from humans. If so, perhaps use of alternative animal species which are more similar to humans (e.g. non-human primates) might afford greater predictive power.
However, a current publication (reference below) has now shown that one species of non-human primate – the cynomolgus monkey – is remarkably resistant to liver injury caused by caused by paracetamol. This finding is important for numerous reasons. Firstly, cynomolgus monkeys are the non-human primates used most commonly to assess drug safety. Secondly, paracetamol is a very widely used drug which, when taken in accidental or deliberate overdose in humans, causes several and potential fatal liver injury. Thirdly, the mechanisms by which paracetamol causes human liver injury has been investigated intensively and is well understood. The key initiating event is its enzymically mediated conversion with cells of the liver to a chemically reactive intermediate, which disrupts normal liver function. This process does not occur at normal therapeutic doses due to drug clearance via alternative metabolic routes, which are saturated following overdosage. Fourthly, a plausible metabolic explanation for the lack of liver injury in the cynomolgous monkey has been identified. This is extensive metabolic detoxification, which occurs to a markedly greater extent at high doses in this species than in humans, or in other species which are susceptible to paracetamol induced liver damage.
Clearly, the increased use of non-human primates in nonclinical safety testing of drug candidates is ethically undesirable and, in view of the substantial cost of such studies, can be expected to increase markedly the cost of drug development – which already is substantial. Therefore such studies should be considered only if they can be shown to be scientifically justifiable and there are not valid alternatives. The publication highlighted above aises significant concern about the scientific validity to humans of drug safety studies undertaken in primates. Conversely, substantial progress has been made in the development of new in vitro and in silico methods (e.g. http://www.ncbi.nlm.nih.gov/pubmed/22646477; http://www.ncbi.nlm.nih.gov/pubmed/24214486), which have the potential to reduce, refine and ideally replace the need for animal studies in the future.
The paper: Hong Yu et al (2014). Metabolism by conjugation appears to confer resistance to paracetamol (acetaminophen) hepatotoxicity in the cynomolgus monkey. Xenobiotica
This paper relates to a statement issued to the press in October 2014. Link.