Toxicokinetics is an essential element of preclinical studies of drugs. As an interdisciplinary discipline between pharmacokinetics and toxicology, toxicokinetics is a bridge and tool for advancing preclinical studies to clinical studies. The primary goal of toxicokinetic studies is to demonstrate the systematic exposure levels of new drugs in test animals during safety evaluation and their correlation with the administered dose and the course over time. Their studies generally include single-dose studies in toxicity studies, multiple-dose studies, tissue distribution studies, genotoxicity studies, carcinogenicity tests, reproductive toxicity studies, and toxicokinetic studies for specific drugs such as biotechnology.
Toxicokinetics is based on pharmacokinetic studies, with the help of its methods and tools, to help evaluate drug safety and regulate research behavior according to GLP. As new drug research progresses, some compounds to be selected (both small and large molecules) are eliminated from the development process because of safety concerns. Therefore, only after adequate preclinical studies of the new compounds have been performed is it possible to consider whether the drug is ready for clinical trials. And toxicokinetic studies have become one of the essential tools of toxicological studies in the safety evaluation of new medicines. We boast professional teams and practical experience in drug safety evaluation and can promise high-quality data and fast turnaround time to support various drug safety evaluations.
Toxicokinetic studies are usually performed with toxicity tests and include the determination of time-course changes in the concentration of prototype compounds or metabolites in plasma (whole blood or serum). The decision of plasma (or whole blood or serum) AUC, C_(max), and C(time) are the most common parameters used to evaluate drug exposure levels in toxicokinetic studies. Exposure is usually assessed regarding non-plasma protein-bound (free-form) drug concentrations.
Toxicokinetic data can be obtained from the entire animal population of a toxicity study, from representative or satellite groups, or individually designed studies. Whole-body exposures can be used to evaluate the animal load to the test substance and help explain similarities and differences in toxicity between animal species, dose groups, and sexes. Exposure can be expressed as plasma (serum or whole blood) concentrations or AUC of the prototype compound or its metabolites. Usually, the content of toxicokinetic studies is as follows:
1, Toxicokinetic studies in single-dose toxicity studies
Toxicokinetic studies in single-dose toxicity studies help determine the choice of test dose regimen and help predict the rate and extent of systemic exposure and duration of the drug during administration. Single-dose toxicity studies are generally in the early stages of preclinical studies of drugs. Bioanalytical methods have yet to be fully established and validated, so conducting more formal toxicokinetic studies at this stage is impossible, only when necessary. This study uses sampling to determine plasma drug concentrations or to be analyzed in samples after selecting the method. Or they are conducting a separate toxicokinetic study after a tough single-dose toxicity test.
2, Toxicokinetic studies in multi-dose toxicity studies
The design of multiple-dose toxicity studies is generally based on the principle that selecting test protocols and test animals should be consistent with pharmacodynamic and pharmacokinetic studies. Multi-dose toxicokinetic studies should be incorporated into the design of the overall toxicity study. Suppose systemic exposure to the drug is difficult to predict. In that case, a multi-dose administration toxicokinetic study should be performed before the long-term toxicity study to observe the difference in concentration between the first and last days of administration and to determine changes in steady-state concentrations and AUC.
Suppose a toxicokinetic study can be performed with a long-term toxicity test. In that case, systemic exposure at appropriate dose levels should be tested in the early phase of the trial. The measurement protocol should be determined in the later stage based on the results of the earlier test, generally measuring drug concentrations after the first and last day of administration of the long-term toxicity test and observing changes in AUC and steady-state concentrations to ensure that the results can explain the results of the toxicity test.
3, Tissue distribution studies
The ICH triad agrees that tissue distribution studies of single-dose administration are an integral part of preclinical drug safety evaluation for the following reasons:
(1) Tissue distribution studies for multiple dose administration are necessary when the half-life of the drug or metabolite significantly exceeds the plasma half-life when it appears or is revealed to accumulate in organs or tissues at a single dose and is two times the time interval between dosing in toxicity tests;
(2) In pharmacokinetic and toxicokinetic studies in which the steady-state level of the drug or metabolite in circulation is significantly higher than the concentration predicted during a single-dose administration study, a multiple-dose tissue distribution study should be considered;
(3) Multiple-dose tissue distribution studies should be considered when critical tissue distribution is associated with histopathological changes in single-dose tissue distribution tests and pharmacological tests to explain the relationship between target organ and tissue distribution of action or toxicity;
(4) When developing targeted-release drugs with specific distribution is desired, multi-dose administration tissue distribution studies are appropriate and necessary.
4, Toxicokinetic studies in genotoxicity studies
Guidelines for genotoxicity studies were designated by the European Community in 1987, Japan in 1989, and the United States in 1993. 1995 the three parties reached a harmonization agenda and adopted the designated guidelines. For compounds with favorable in vitro genotoxicity tests, in vivo drug exposure levels should be demonstrated by different methods.
By measuring the concentration levels of drugs and related substances in plasma or whole blood, bone marrow drugs are determined, and tissue drug exposure is evaluated by autoradiography. Compounds that are negative in vitro (no genotoxicity) are subjected to in vivo systemic drug exposure tests to demonstrate drug exposure levels in target organ tissues. For negative in vivo genotoxicity results, toxicokinetics can better describe the systemic exposure level of the drug and tissue-specific drug exposure for the animal species used.
5, Toxicokinetic studies in carcinogenicity testing
According to the 1990 guidelines for toxicity studies, Japan requires that drugs used for more than six months, the United States requires that drugs used for more than three months, and the European Community requires that medicines used for six months and more than six months be tested for carcinogenicity. It is now agreed that all drugs administered for six months should be subjected to carcinogenic toxicity testing.
Toxicokinetic studies in carcinogenicity trials provide data to assist in the rational selection of animals, methods of administration, and doses to be administered in carcinogenicity trials. The ideal test design should ensure that the amount used in the carcinogenicity test produces a range of systemic toxicities. The systemic drug exposure to the prodrug or its metabolites at appropriate dose levels is evaluated at different stages of the carcinogenicity trial. Toxicokinetic data can be helpful for dose selection without clinical information and for understanding the interpretation of toxicity due to nonlinear kinetic processes.
6, Toxicokinetic studies in reproductive toxicity
After completing pharmacokinetic studies in animals, specific information was obtained, laying the foundation for selecting animals and dosing regimens to carry out reproductive toxicity studies of drugs. The pharmacokinetic processes in pregnant animals during gestation and lactation differ from those in normal animals. In reproductive toxicity tests, it is generally valuable to study the toxicokinetics of drugs with embryotoxicity and neonatal toxicity, and the information provided is meant to explain such toxicity. Therefore, maternal, fetal, and neonatal specimens of different days should be collected in the test to determine the concentration changes of drugs or active metabolites and to obtain systemic exposure data.
7, Toxicokinetic studies of biotechnology drugs
Pharmacokinetic and toxicokinetic studies of biotechnological drugs are not evaluated by applying general drug study methods. Changes in their kinetics due to immunologically involved clearance mechanisms may affect pharmacological effects. Whenever possible, toxicity studies should be conducted with toxicokinetic studies to monitor drug exposure. Trials should be designed using drugs consistent with clinical application, by the clinically expected route of administration and dose.
Toxicokinetic studies of single-dose dosing and multi-dose dosing can be studied as appropriate. The biological activity of radiolabeled drugs should be maintained when performing tests with them. The misleading effect of the shedding of radioactive substances on interpreting results should be considered.
Toxicokinetics in preclinical studies of drugs can explore the pattern of occurrence and development of drug toxicity, understand the distribution of drugs in animals and their target organs, and provide a basis for further other toxicity tests, as well as for future clinical use of drugs and the diagnosis and treatment of drug overdose.