Medicilon synthesizes reference compounds, intermediates, drug candidates, impurities, metabolites and other small molecular chemicals for its customers. Its scale can range from milligrams to kilograms (including GMP quality). Our team is proficient in new route design and route optimization. With proficiency in problem solving and high project success rate, we have the ability to provide customers with the following high-quality customized chemical synthesis services:
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Drug metabolism means that the drug is affected by the intestinal flora or the enzyme system in the body after the absorption process or enters the systemic circulation. The process of structural change is called metabolism or biotransformation, and its product is a metabolic product.
Route of administration: Metabolism is related to the distribution of drug metabolizing enzymes in the body and the blood flow of local organs and tissues. The route of administration is one of the important factors affecting drug metabolism.
Dosage and dosage form: metabolism is related to the distribution of drug metabolizing enzymes in the body and the blood flow to local organs and tissues. The route of administration is one of the important factors affecting drug metabolism.
The influence of the optical isomerism of drugs: Most of the metabolic reactions of drugs in the body are enzyme reactions. Therefore, the collective metabolic capacity of drugs mainly depends on the vitality and quantity of various drug metabolizing enzymes in the body.
Enzyme or enzymatic action: Enzyme inhibitors are substances that slow down metabolism, and enzyme inducers are substances that accelerate metabolism.
(1) Drug metabolism in vitro Study on metabolic stability of liver microsomes (mouse, rat, dog, monkey or human)
Hepatic cell metabolic stability (mouse, rat, dog, monkey or human)
Metabolic structure analysis and identification (microsomes, hepatocytes)
Quantitative analysis of metabolites (microsomes, hepatocytes)
Active metabolite research
Drug Metabolism Interaction (DDI)
Identification of main metabolic enzymes of drugs
Study on the phenotype of CYP450s
Plasma/protein binding assay
(2) Study on drug metabolism and pharmacokinetics in vivo
In vivo pharmacokinetic experiments (mouse, rat, dog, monkey)
Pharmacokinetic study of single and multiple administrations of different administration routes (intravenous injection, oral administration, subcutaneous and intramuscular injection)
Bioavailability study (F%)
Study on the distribution of drugs in various tissues in the body
Drug excretion studies
Study on the bioavailability and bioequivalence of pharmaceutical preparations
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Guiding principles for the safety testing of drug metabolites
I. Overview
Non-clinical studies of drug safety usually consist of standard animal toxicology tests. These tests usually include the evaluation of drug exposure, mainly the plasma concentration of the parent drug. Under normal circumstances, the plasma drug concentration and system exposure obtained in non-clinical trials are usually compared with the system exposure in humans, the potential risks suggested by the results of non-clinical trials are evaluated, and the risk control in clinical trials is guided. When the metabolic characteristics in the human body are similar to the metabolic characteristics in at least one animal species used in non-clinical trials, this test mode is generally considered feasible and sufficient. However, the metabolic characteristics of different animal species may be qualitatively and quantitatively different, and there are cases where clinically relevant metabolites have not been determined or fully evaluated in non-clinical safety trials. If a metabolite only appears in the human body but does not exist in the tested animal species, or the exposure ratio of a certain metabolite in the human body is higher than that in the animal species using the parent drug for standard toxicology tests At this level, the safety of metabolites is worthy of attention, and non-clinical safety evaluation of metabolites should be considered.
Background Information
Under normal circumstances, preclinical safety tests do not require the evaluation of metabolites in animals. Therefore, the role of metabolites in overall drug toxicity is often unclear. The lack of evaluation of the role of metabolites in drug toxicity may be partly due to the lack of sensitivity of the analytical methods used to detect and identify the characteristics of the parent drug metabolites. With the advancement of technology in the past 10 years, the analysis and detection capabilities have been significantly improved. It is now possible to detect, identify and characterize metabolites, which will help to better understand the status of metabolites in drug safety evaluation.
Drugs that enter the body are usually biotransformed through phase I and phase II metabolic pathways. Depending on the nature of the chemical reaction involved, the metabolites produced by the phase I reaction are likely to be chemically reactive or/and pharmacologically active, so safety assessment may be more required. Active metabolites may bind to therapeutic target receptors or other receptors, or interact with other targets (such as enzymes and proteins), causing unintended effects. This problem is especially important when metabolites are formed only in the human body. However, the occurrence of metabolites that exist only in the human body but not in the species of laboratory animals is extremely low. A more common situation is that the proportion of metabolic products formed in the human body is much higher than the proportion of the metabolic products of the parent drug in animal safety tests, due to the qualitative and/or quantitative differences in the metabolic characteristics of the human body and the animal . If it is determined in the toxicology test of the parent drug that at least one experimental animal species has a sufficiently high exposure level to form a specific metabolite (approximately or higher than human exposure), the metabolite may be considered to be of overall toxicity The role has been determined. See Appendix A for the decision flowchart of the safety evaluation of metabolites.
The active intermediates produced by metabolism are often difficult to detect and measure because of their short half-life. However, they can form detectable and stable products (such as glutathione conjugates), and therefore may not require further safety evaluation of the active intermediate. The combined reaction of II usually increases the water solubility of a compound and loses its pharmacological activity, so no further evaluation is needed. However, if the combined reaction forms a toxic compound such as acetylglucuronide, further safety assessment may be required.
If the study finds that the metabolite has no pharmacological activity on the target receptor, this does not ensure its non-toxicity, and the metabolite may also need to be evaluated for safety in non-clinical toxicology tests. See Appendix B for examples.
Purpose and scope of application
This guideline focuses on drug metabolites that require non-clinical toxicity evaluation, and provides recommendations for when and how developers can identify a high percentage of drug metabolites and study their safety characteristics.
This guideline applies to new small molecule chemical drugs. This guideline does not apply to those anti-tumor drugs that need to be considered for risk-benefit evaluation. For safety tests on anti-tumor drug metabolites, refer to the ICH S9 guidelines.
Registration applicants can communicate with the drug review department on the safety evaluation of metabolites in the development of specific drugs.
General considerations on the safety test of metabolites
The differences in drug metabolism between animal species and humans used in non-clinical safety assessments should be confirmed as early as possible in the drug development process. For example, after obtaining human pharmacokinetic data, it is determined whether the safety evaluation of metabolites needs to be carried out as soon as possible by comparing the pharmacokinetic information. The discovery of a high proportion of drug metabolites (Disproportionate drug metabolite) in the late stages of drug development may lead to delays in drug development or marketing.
In general, safety evaluation should be considered when the metabolite only appears in the human body, or the level of the metabolite in the human body is much higher than the level in known or evaluated animal species. If the level of metabolites in the human body is higher than 10% of the total drug exposure at steady state, it will usually cause safety concerns. Metabolite levels are usually expressed in terms of area under the curve (AUC), but sometimes they are expressed in terms of peak concentration (Cmax).
(1) General methods for evaluating the safety of metabolites
If the metabolic product found in the animal does not exist in the human body, it means that the toxicity caused by the product observed in the animal species may not be relevant to the human body. Conversely, if the metabolite found during clinical development does not exist in the species of the experimental animal, or the level in the animal is much lower than the human level, it is recommended to conduct further animal tests to determine the potential toxicity of the metabolite.
In this case, consider the following two methods to evaluate the safety of drug metabolites. The first method is to determine an animal species in the routine toxicology test, on which a sufficient exposure level of the metabolite (equivalent or higher than human exposure) can be formed, and then in the animal Study drug toxicity in species. The second method is that if a related animal species that forms the metabolite cannot be determined, the metabolite can be synthesized and further safety evaluations can be carried out by incorporation or direct administration. The above tests need to establish analytical methods that can identify and detect the metabolite in nonclinical toxicology tests.
As we all know, there are difficulties in the synthesis of specific metabolites, and the direct administration of metabolites also has its inherent complexity. Direct administration of metabolites to animals may lead to subsequent metabolism, which may not reflect the actual clinical situation, which complicates the evaluation of toxicology. Administration of metabolites may lead to new toxicity that has not been observed in parent drug trials. However, despite such complex problems, the detection and evaluation of potential toxicity of drug metabolites is still important to ensure the clinical safety of drugs. . Determining whether to conduct a direct metabolite safety test should be based on a comprehensive evaluation of parent drug data and metabolic information.
(2) Identification of metabolites
In the process of drug development, it is necessary to determine the metabolic characteristics of drugs. The determination of metabolic characteristics can be accomplished through in vitro and in vivo test methods at different stages of development. In vitro tests can use liver microsomes, liver slices, or hepatocytes from different animals and humans. In vitro tests should usually be conducted before clinical trials begin. In vivo metabolic tests in non-clinical animal species should usually be conducted early in the development of the drug. The results can confirm the results obtained in in vitro tests or suggest qualitative and/or quantitative differences in metabolism between animal species, which may Bring security concerns. The human body’s in vivo metabolic tests are usually conducted at a relatively late stage of drug development, but it is still recommended that the human body’s in vivo metabolic studies be conducted as soon as possible.
For the exposure level of metabolites in non-clinical experimental animals that is much lower than that of humans, whether the exposure is sufficient should be analyzed by specific problems. Normally, the system exposure is analyzed by measuring the drug concentration in serum or plasma at steady state. However, if for some reason it cannot be measured in the plasma of the test animal, the level of metabolites in other biological matrices can be determined to verify the adequate exposure, such as urine, feces or bile.
(3) General considerations for the design of non-clinical trials
When designing a non-clinical trial for a high proportion of drug metabolites, the following factors need to be considered: similarity of the metabolite to the parent molecule, pharmacological or chemical classification, solubility, stability in the gastric juice environment, phase I or phase II metabolism Product, the relative amount of exposure in humans and exposure in animals.
Other factors to consider include drug designation indications and patient populations [for example, non-clinical trials can be simplified for indications for severe diseases, such as amyotrophic lateral sclerosis (ALS)]. When designing non-clinical trials of metabolites, it is also necessary to consider the planned medication course (short-term, medium-term or long-term medication) and the exposure level at the therapeutic dose.
Safety test of recommended metabolites
Non-clinical trials of drug metabolites that need to be evaluated for safety should comply with GLP. The following tests may be required to evaluate the safety of a high proportion of drug metabolites.
(1) General toxicology test
In general toxicology tests, the potential toxicity of a high proportion of drug metabolites should be evaluated, and the toxicity comparison between the metabolite and its parent drug should be performed. For the time limit of general toxicological tests for direct administration of metabolites, refer to relevant domestic guidelines and ICH M3 (non-clinical safety tests required to support drugs for human trials) technical guidelines. The toxicity of metabolites should be evaluated at several times human exposure or at least at levels comparable to those detected in humans. It is recommended to use the clinical route of administration of the parent drug. However, if a high proportion of drug metabolites can be exposed, other routes of administration can also be used. If the clinical route of administration is oral, it is important to confirm the stability of metabolic products in the gastric juice environment. To ensure adequate exposure of a high proportion of drug metabolites, the above tests need to include toxicokinetic studies.
(2) Genotoxicity test
An in vitro test to detect point mutations and another test to detect chromosomal aberrations are needed to evaluate the potential genotoxicity of metabolites. These tests can refer to SFDA “Guidelines for Technical Research on Drug Genotoxicity”. If one or both tests are suspicious and/or positive, a complete genotoxicity standard combination test may be required.
(3) Embryo-fetal development toxicity test
If the intended drug-using population includes women with fertility potential, an embryo-fetal developmental toxicity test of metabolites is required. Based on the results of the general toxicology test and embryo-fetal developmental toxicity test, on the basis of specific analysis of specific issues, other reproductive toxicity tests may be required. These tests can refer to SFDA “Reproductive Toxicity Research Technical Guidelines”. In some cases, embryo-fetal developmental toxicity tests can be conducted only in one animal species that can form the metabolite.
(4) Carcinogenicity test
The drug has been used continuously for at least 6 months, or intermittent medication is required for the treatment of chronic or periodic recurrent diseases. If the carcinogenicity test of the parent drug cannot fully evaluate the carcinogenic potential of the metabolite, the carcinogen of the metabolite should be performed Sex test. These tests can refer to SFDA “Technical Guiding Principles for the Necessity of Drug Carcinogenicity Tests” and foreign technical guidelines for carcinogenicity tests.
Time schedule of safety research
It is necessary to confirm the high proportion of drug metabolites that may exist in the human body as soon as possible, which can provide evidence for the rationality of non-clinical trials, help clarify and formulate clinical trial plans, and avoid delays in the process of drug development. Usually, in vitro tests are used to predict the difference in drug metabolism between animals and humans, and then whether the safety test of drug metabolites needs to be carried out is based on the difference between human and animal metabolism. If in vitro metabolic studies suggest that there is a high proportion of human drug metabolites, it may be considered to carry out metabolic studies of animal and human isotope labeling methods to provide a basis for conducting preclinical safety studies of high proportion of drug metabolites.
If metabolite toxicology tests are required, these tests should be completed before the start of a large-scale clinical trial and a test report should be submitted to the drug review department.
To optimize and accelerate research and development for other serious or life-threatening diseases including tumor diseases (such as ALS, Stroke, HIV) medicines, for those medicines that have significant therapeutic benefits, as well as medicines for diseases that still lack effective treatment, the number and type of non-clinical trials of metabolites can be adjusted according to the principle of specific analysis. When treating advanced cancer patients, these metabolites do not require a separate toxicological evaluation. In this case, the sponsor should contact the relevant drug review department for discussion.
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