In the process of new drug development, candidate drugs must undergo a comprehensive assessment of their acute, chronic, developmental and reproductive toxicity and carcinogenicity before entering the clinical trial stage to ensure the effectiveness and safety of the drug after it is administered to the human body.
Because laboratory animals usually have similar molecular targets and metabolic pathways to humans, they are used in preclinical studies of drug candidates. Among them, especially drug toxicology research (toxicology experiment) requires the use and sacrifice of a large number of laboratory animals.
Normally, preclinical evaluation of drug candidates will use one rodent (rat or mouse) and one non-rodent (usually rabbit, dog, pig, and monkey).
Non-rodent animal test results can not only significantly increase the success rate of clinical trials of candidate drugs, but also provide higher safety guarantees for drugs after clinical use.
In the history of drug research and development, the famous thalidomide (trade name “Thalidomide”, which caused baby seal fetus after being taken by pregnant women) occurred, in addition to the imperfect regulatory system for drug research and development, it was also inseparable from the inappropriate choice of experimental animals.
“Thalidomide” victim, child with seal limb syndrome
The pharmaceutical company that developed “Thalidomide” used pregnant rats to conduct animal experiments to evaluate its effects on pregnant women before applying for the drug to be marketed, but what they did not know at the time was: “Rats and primates are different. The lack of an enzyme that can convert “thalar” into a toxic product will not cause teratogenesis.”
The “Thalidomide” incident has made the industry notice the difference in the response of different species to drugs. Food and Drug Administration (FDA)-based drug regulatory agencies around the world have also begun to standardize the preclinical evaluation rules of drugs, and require the use of two or more experimental animals, including non-rodents, to conduct preclinical research.
Among them, the selection of non-rodent experimental animals for toxicology experiments is particularly important, and the following factors need to be considered:
The selected experimental animal species must be a species that can accomplish the preset scientific goals. Theoretically, a species that is more similar in anatomy or physiology to humans is more closely related to the pharmacological or toxic reaction of the tested compound or biological macromolecule, but in practice, it is necessary to conduct experimental animals from the following perspectives s Choice.
Experimental animal species that have been proven effective in previous studies.
The selection is based on the published absorption, distribution, metabolism and excretion data of the candidate compound or a compound similar to the candidate drug. Select experimental animal species that have a high correlation between previous toxicology experience and human research.
Experimental animals that have had experience or have proved through preliminary experiments that candidate drugs can produce drug curative effects in this species.
Select species that have no immune response to candidate drugs. This is particularly important for biomacromolecule candidates.
In the absence of any reference data, a small number of experimental animal tests on multiple species can be considered, and selections can be made based on the test results.
Ethical considerations need to adhere to the principles of substitution, reduction and optimization under the premise of achieving scientific goals.
Try to choose species with low perception ability to reduce the pain of experimental animals.
When other species are available, do not choose companion animals such as cats and dogs and non-human primate laboratory animals as much as possible.
When using non-human primate experimental animals, it is necessary to explain the reason and rationality of their use. When non-human primate laboratory animals must be used, the principle of using New World monkeys (marmosets) should be followed.
The scientific and ethical orientation of experimental animal selection
Scientific considerations often point in different directions from ethical considerations, and ethical considerations will be affected by the emotional preferences of the public.
When experimenting with dogs as more popular pets, it is usually more stressful than using miniature pigs, but you can hardly say that the perception ability of miniature pigs is weaker than that of dogs. There is also no evidence that marmosets are more perceptive than dogs. The size of marmosets is much smaller than dogs and miniature pigs, and fewer candidate compounds can be used in drug experiments with them.
In the early stage of new drug development, the amount and speed of candidate compound synthesis is an important rate-limiting link in new drug development. Therefore, the use of marmosets to carry out animal experiments can significantly accelerate the process of new drug development. In addition, there are cultural differences in ethical considerations, and different countries and regions have their own judgment standards, which are difficult to unify.
The main focus of practical considerations is the availability of resources and existing data.
For example, marmosets have not formed large-scale breeding in my country, so it is difficult to use them in a large number of animals of uniform age and weight to complete toxicological experiments.
In Western countries, it is obvious that the ethical pressure of using small pigs such as Göttingen for animal experiments is much less than that of choosing beagle dogs, but in practice, it is necessary to face the basic clinical and pathological and toxicological data of small pigs. Less than the reality of the Beagle.
Similarly, although my country has bred many small pig breeds such as Wuzhishan, Banna and Bama, the pathological and toxicological data of these new breeds of small pigs are even worse than those of Göttingen, which have been widely used. sound.
When selecting experimental animals for drug preclinical research, we are always faced with “We need to understand human response to drugs in order to select the species closest to human drug response, but at the same time we need enough animal experimental data to understand humans’ response to drugs. Drug response” dilemma.
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