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Preclinical Toxicological Safety Evaluation of Biological Drugs

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Toxicology Safety Evaluation of  Biological Drugs

Biological drugs is one of the fastest-growing sub-sectors in the pharmaceutical industry in recent years. From the global drug sales rankings in the past few years, it can be seen that the proportion of biopharmaceuticals among the top 10 drugs sold has increased year by year. In 2017, seven of these were biomacromolecule drugs, fully demonstrating the market’s recognition of biologic drugs. In the past few years, China’s biopharmaceutical market has been in a stage of rapid development, and its growth rate has surpassed that of the global market. It is expected that it will continue to grow strongly in the future.

Toxicology safety evaluation is a bridge between pre-clinical and clinical, and it is an important part of the non-clinical safety evaluation process of drugs. A comprehensive understanding of toxicological data is of great significance to clinical trial design and prompting the safety of human medication.
Different from small-molecule chemical drugs, macromolecular biopharmaceuticals have unique species specificity, immunogenicity, and multiple tissue affinity, etc. The toxicological evaluation of biopharmaceuticals emphasizes the principle of specific analysis of specific problems and evaluates them. Security. For conventional biological drugs, generally speaking, the toxicological tests to be carried out before IND are summarized as follows.

Acute toxicity test

The dose-response relationship between dose toxicity can be obtained through acute test, which provides a reference for long-term toxicity test dose selection. The acute toxicity test can be combined with the general pharmacological test. It may also be considered to incorporate general pharmacological parameters into the design of these experiments. For the acute toxicity test, the FDA does not require it. However, it is currently required by the CFDA. If the test is missing, it may not be accepted.

Long-term toxicity test

The long-term repeated dosing toxicity test is the most comprehensive, the most informative, and the most meaningful for clinical guidance. The purpose of the test is to establish toxic target organs, dose-response relationships, NOAEL values, etc. Safety pharmacological tests, immunogenicity/toxicity tests (lymphocyte phenotype, cytokine immunoglobulin and complement analysis, etc.) are usually combined in long-term toxicity tests.

The period of repeated dosing

The period of repeated dosing should be determined according to the period of clinical trials, dosing frequency and kinetic parameters, and can range from four weeks, 13 weeks to 26 weeks. Due to the relatively long half-life of macromolecules, the frequency of administration is usually once a week, and the recovery period ranges from four to ten weeks, depending on the clearance rate of the drug.


Immunogenicity refers to the specific adaptive immune response to the antigen produced by the body after being stimulated, involving cellular and humoral immune responses, as well as innate immune responses. Anti-drug antibodies affect the exposure of the drug, and are usually collected once before administration, during the middle of the administration, at the end of the administration, and during the recovery period. The immunogenicity results are used to interpret the toxicological data, but the results are of little reference value for pushing to humans. Immunosuppression and immunostimulatory response are immunotoxicity worthy of attention. In the repeated dosing test, we focus on the observation of immunological indicators such as histopathological examination of immune organs, weighing of lymphoid organs, and hematology (including white blood cell classification), which provide important references for the design of clinical research programs.

Safety pharmacological test

Safety pharmacological test. The core combination of safety pharmacological tests includes the evaluation of the central nervous system, respiratory system, and cardiovascular system. The test can be conducted separately, but is generally integrated in a single-dose or repeated-dose toxicity test. Attention should be paid to the selection of relevant animal species. Because of their lack of correlation, rodents are rarely used.

Organize crossover trials

Tissue cross-testing is generally only required for monoclonal antibodies, and the purpose is to check whether the biological drug being evaluated has cross-reactivity with various tissues of humans and animals. The test uses direct immunohistochemical staining to evaluate the biotinylated test substance (Biotin-TA) and biotinylated reference substance (Biotin-CA) and fresh frozen normal human or animal (cynomolgus monkey/rat) tissue To determine whether there is cross-reactivity.

Local tolerance and allergy test

Local tolerance tests are required for injectable biological drugs, including active allergies, passive allergies, and local irritation tests. The local irritation test can be evaluated in a preliminary acute or repeated toxicity test. The purpose of the hemolytic test is to observe whether the test substance can cause hemolysis and red blood cell aggregation, including in vivo/in vitro hemolysis test.

In the biopharmaceutical toxicological safety evaluation, special attention should be paid to the selection of animal species. Generally, two related animal species should be considered, but when only one related animal can be identified, the use of one related animal species is also accepted. Special attention should be paid to avoid the use of unrelated animal species, because unrelated animals may mislead drug safety reviews. If it is confirmed that there are no related animal species, the use of related transgenic animals expressing human-derived receptors should be considered. In addition, even if the short-term toxicity test must use two animals to determine toxicity, the subsequent long-term toxicity test may still have reason to use one animal, for example, when the short-term toxicity test results of the two animals are similar.

When designing the dose, the dose should reflect the dose-toxicity relationship, including a toxic dose and a dose for which no adverse effects have been observed (NOAEL). For some products with little toxicity, it is impossible to specify a specific maximum dose. When selecting high doses, it is possible to consider reaching approximately 10 times the clinical dose exposure or 1000 mg/kg as the maximum dose.

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