Understanding Reproductive Toxicity Studies: Types and Applications

2020-12-03

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The Study of Drug Reproductive Toxicity Test

Medicine is a double-edged sword. It can cure diseases, save people, and produce adverse reactions that damage human health. Reproductive toxicity studies are one of the essential contents of drug toxicity research, which refers to the damage of drugs to reproductive function and ability and the unfavorable mailbox for offspring. For drugs to be used in humans, animal reproductive toxicity tests need to be comprehensively considered based on the intended indications and characteristics of the test substance.

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Failure of a compound at the Clinical stage is very costly, and considerable efforts are made to eliminate potentially toxic compounds much earlier in the drug discovery process using in vitro or even in silico methods.

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Reproductive toxicity of drugs is significant for guiding the safety of the clinical medication. The reproductive toxicity of drugs has two characteristics: sensitivity to the toxic effects of drugs at a specific dose. Before damage to other systems occurs, a particular part of the reproductive process may have been damaged; the reproductive toxicity of drugs is not only manifested in drug exposure. The body itself can also affect offspring. Therefore, reproductive toxicity can occur both during pregnancy and during pregnancy and lactation. The drug reproductive toxicity test should implement GLP specifications. There are many research methods for the reproductive and developmental toxicity of drugs. Commonly used reproductive toxicity test programs include the following three parts of joint research:

The Study of Drug Reproductive Toxicity Test

What are 3 types of reproductive toxicity studies?

(1) Segment Ⅰ (fertility and early embryo development):

Also called the general reproductive toxicity test studies the effects of drugs on the entire reproductive process. It evaluates whether germ cells adversely affect conception ability, reproductive system, and offspring after drug exposure. At least one animal is used in selecting experimental animals, and rats are the first choice. Fertility and early embryo developmental toxicity tests are an essential part of drug reproductive toxicity research, and they are also indispensable in developing innovative drugs. The staff of Medicilon's reproductive toxicity research service platform is composed of a professional technical team led by senior domestic reproductive toxicity experts with 30 years of research experience; the animal laboratory was jointly established by Medicilon and MPI Research (American Toxicology Research Company), Passed the International Laboratory Animal Assessment and Approval (AAALAC) and reached the GLP dual standards of FDA and CFDA.

In drug development, fertility and early embryo development play an important role. Before a drug can be approved for human use, it must undergo a series of preclinical studies to evaluate its safety and efficacy.

In preclinical studies, the effects of a drug on fertility and early embryo development are typically assessed using animal models. These studies typically include tests for reproductive and developmental toxicity to ensure that the drug does not harm fertility or early embryo development.

This can provide valuable information on the potential reproductive and developmental risks associated with a drug and the mechanisms underlying any observed effects. They can also help identify the critical windows of development during which exposure to a drug may have the greatest impact.

Once a drug has passed preclinical testing, it can proceed to clinical trials in humans. In these trials, the effects of the drug on fertility and early embryo development are closely monitored, particularly in women of childbearing potential. If any reproductive or developmental concerns arise during clinical testing, additional studies may be conducted to understand the risks better and inform the drug's safe use.

(2) Segment Ⅱ (embryo-fetal development):

The purpose is to assess the harmful effects of exposure to the test substance from the blastocyst implantation to the closure of the hard palate (the organogenesis period) on pregnant females and the development of the embryo-fetal body. The consequences of embryo-fetal developmental toxicity are relatively more severe, and we should pay more attention to the results of this test section. If various animals are used for testing, it may provide an adequate test basis when the test results are extrapolated to humans. The test usually uses two animals, one is a rodent, and rats are recommended, and the other is a non-rodent, and rabbits are recommended.

Embryo-fetal development studies help to evaluate the safety of drugs during pregnancy and assess their potential impact on fetal development. These studies are typically conducted in animal models, such as rats or rabbits, to evaluate the potential risks to human fetal development.

The primary goal of embryo-fetal development studies is to identify any adverse effects of a drug on fetal development, such as developmental abnormalities or growth retardation. These studies also aim to determine the dose-response relationship between the drug and any observed adverse effects and identify the critical windows of exposure during fetal development when a drug may be most harmful. The results of embryo-fetal development studies inform the dosing and safety recommendations for pregnant women taking the drug. In some cases, if the risks of a drug to fetal development are deemed too great, the drug may not be approved for use in pregnant women or may be recommended only under certain circumstances.

Embryo-fetal development studies are typically conducted in two phases: the first phase is the embryo-fetal toxicity study, which evaluates the potential for a drug to cause developmental toxicity in animal models. This study is typically conducted during early fetal development and assesses the impact of the drug on fetal growth, morphology, and development.

The second phase is the embryo-fetal development study, which evaluates the potential impact of a drug on fetal development throughout pregnancy. This study assesses the impact of the drug on fetal growth and development, as well as maternal and fetal toxicity.

(3) Segment Ⅲ (developmental toxicity test before and after birth)

Perinatal toxicity test to evaluate the effects of drugs on the growth and development of fetuses after birth, to detect the adverse effects of drug administration on pregnant/lactating females, and the development of embryos and offspring from embryo implantation to pup weaning. These tests are typically conducted in juvenile animals, and they assess the impact of the drug on growth, behavior, and organ function after birth. The results of these tests are used to inform the dosing and safety recommendations for infants and young children taking the drug. At least one animal is used in the selection of experimental animals, and rats recommend.

In addition to the traditional animal testing methods, new in vitro developmental toxicity testing methods are being developed. These in vitro models utilize human stem cells and tissue cultures to evaluate the potential toxicity of drugs on fetal development.

Reproductive toxicity research of innovative drugs adopts the conventional three-stage test design. The current reproductive toxicity test research of drugs divides into the above three-stage. When adopting the segmented test design, pay attention to the animal's adulthood from conception to pregnancy. The pups are administered at all stages of sexual maturity. The observation should continue for a complete life cycle (from the beginning of one generation to the next). In actual operation, a single (entire course) test design and a two-stage test design can be used for rodents according to the test substance's indications and characteristics.

In the study of reproductive drug toxicity, other test schemes can also be considered comprehensively according to the characteristics of the test substance, intended indications, and clinical medication.

Overall, reproductive and developmental toxicity studies help to identify potential risks to the developing fetus before and after birth, help to ensure the safety of drugs during pregnancy, and protect the health of both the mother and the developing fetus, as well as infants and young children who may be exposed to the drug after birth. So it is an essential part of drug development.