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Status and Prospects in Drug Toxicokinetics

2021-03-01
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As a cross-discipline of pharmacokinetics and toxicology, toxicokinetics has now become an important content of non-clinical drug research and a bridge and tool for advancing preclinical research to clinical research.

This article reviews the basic content of domestic toxicokinetic research at this stage, focusing on the guiding principles of toxicokinetic research, precautions in various aspects of experimental design, biological analysis methods, kinetic parameters, and toxicokinetic research in clinical practice. The application in pre-safety evaluation, the difference between small molecule drugs and macromolecular drugs, and the progress of foreign toxicokinetics research.

toxicokinetics

Toxicokinetics (TK) is an emerging discipline at the stage of drug development and research. It has become an important part of new drug non-clinical research and a common method for new drug development.

Toxicokinetics is a cross-discipline of pharmacokinetics (PK) and toxicology. It uses the principles and methods of pharmacokinetics to quantitatively study the absorption, distribution, and metabolism of drugs in animals at toxic doses. , The process and characteristics of excretion, and then to explore the law of occurrence and development of drug toxicity, to understand the distribution of drugs in animals and their target organs, to provide a basis for further other toxicity tests, and to diagnose and treat future clinical drug use and drug overdose Provide evidence.

TK is different from pharmacokinetics in that the doses of its study drugs for absorption, distribution, metabolism, and excretion are much higher than those for usual drug screening or drug therapy.

Under toxic doses, the transport system and metabolic enzymes in the body may become saturated, the protein binding ratio may change, and the overall response of the physiological system may also change.

Therefore, TK does not simply describe the basic kinetic characteristics or toxic reaction events of the test substance, but more scientifically establishes concentration-response relationships and concentration-effect relationships.

In order to better use “exposure in the test substance” to build a bridge between “dose” and “toxicity of the test substance”, when discussing the toxicokinetic results, it should be understood that: the toxicity of the test substance is caused by The pharmacological effect is produced with the increase of dose, or from other mechanisms different from the pharmacological action mechanism; Does the toxic reaction of the test substance come from the test substance itself or its metabolites; Plasma protein binding and test The relationship between the toxic reaction of the substance; the correlation between the blood concentration of the test substance and the concentration in the organ that produces the toxic reaction, etc.

Traditionally, the safety window of a drug refers to the ratio of no observed adverse effect level (NOAEL) to the clinical human dose. However, it is converted to animal dose (mg·kg-1) The dosage of the medicine for human body has certain limitations.

It is now generally believed that better extrapolation of animal toxicity data to human data should be based on TK exposure evaluation, rather than a simple dose ratio. Therefore, it is recommended to use the ratio of animal non-toxic exposure to clinical human exposure to calculate the safety window. .

For innovative drugs, TK research has obvious value in the following aspects: Describe the relationship between the systemic exposure of the test substance in the toxicity test and the dose and time of the toxic reaction; Describe the extension of exposure after repeated administration The influence of metabolic processes, including the influence on metabolic enzymes (such as the induction or inhibition of drug-metabolizing enzymes); explain the toxicological findings or changes of the test substance in the toxicity test, and evaluate the test substance in different animal species, gender, and age , The body state such as the toxic reaction of the disease or pregnancy state; support the selection of animal species and medication plan for non-clinical toxicity studies; analyze the predictive value of animal toxicity performance for clinical safety evaluation, such as liver toxicity or kidney damage caused by drug accumulation, It can provide quantitative information for subsequent safety evaluation; comprehensive drug efficacy, exposure, toxicity and exposure information to guide the design of human trials, such as initial dose, safety range evaluation, etc., and guide clinical safety monitoring according to the degree of exposure; In some cases, short-term toxicity tests (1 to 3 months) accompanied by TK research can better support the entry of drugs into early clinical trials, help reduce the safety risks of clinical trials, and shorten the drug development cycle.

Some of the animal testing and sample analysis in TK research are done in non-clinical research institutions; some are done in non-clinical research institutions for animal administration and sampling, while sample analysis and data processing are done in the biological analysis laboratory.

In any case, the sample analysis and data processing of TK research must comply with the technical requirements of the “Technical Guidelines for Non-clinical Pharmacokinetic Research of Drugs” and strictly follow the GLP.

1 Guiding Principles

my country promulgated the “Technical Guidelines for Drug Toxikinetic Research” in May 2014, which mainly refers to the format and content of the International Conference on Harmonization (ICH) S3A of the technical requirements for human drug registration.

ICH S3A is the guiding principle coordinated by the ICH three parties (EU, Japan and the United States).

According to the ICH procedure, ICH S3A was drafted by the ICH Expert Working Group (Security) and submitted to the management for discussion and negotiation. On October 27, 1994, it was recommended by the ICH Preparatory Committee to the European Union, the United States and Japan at the fourth stage meeting of the ICH procedure. Adopted by the administrative department of the United States, it was published on the Federal Register (60FR11264) of the US FDA in March 1995, which is suitable for chemical drugs and biotechnology drugs.

2 Notes on experimental design

The design of the dosing protocol of the TK test should refer to the toxicity test research protocol, including dose, route, animal species selection, dosing frequency, period, etc. However, some details of the protocol design should be paid attention to, such as sample collection.

1. Laboratory animal selection

An ideal laboratory animal should have the following characteristics: ① The metabolism of the test substance is similar to that of the human body. ② Sensitive to the test substance. ③ There are a lot of historical control data, the source, strain, and genetic background are clear.

Before repeated administration toxicity test accompanied by TK, appropriate test methods should be adopted to select the species or strains of experimental animals.

From the perspective of fully exposing the toxicity of the test substance, using different species of animals for testing can obtain more sufficient safety information.

Innovative drugs, especially small molecule drugs, should be tested with at least two species of mammals. Generally, one species of rodent and one species of non-rodent should be used.

Generally, rats are preferred for rodents, and Beagle dogs are preferred for non-rodents.

Normally, healthy adult animals of two sexes are used for testing, with half males and half males.

The animal’s body weight at the time of initial administration should not exceed or fall below 20% of the average body weight.

The age of the animal should be determined according to the test period and the clinical population to be used. Generally, rats are 6-9 weeks old, Beagle dogs are 6-12 months old, and monkeys are 3-5 years old. The age of the animals should be as close as possible, indicating the animal when the drug is started. age.

Animal species and strains should be consistent with other toxicity tests.

In the experiment, the appropriate number of animals and dose groups should be used to estimate the systemic exposure.

In general, it is recommended that each dose group of the test substance be at least 4 animals per sex.

If there is evidence that the test substance has a significant difference in toxicity between sexes, animals of sensitive sex can be selected in the experiment.

For macromolecular drugs, follow the above principles and the principle of case by case.

2. Test substance

Chemical drugs: The test substance should be a sample with relatively stable technology, purity and impurity content that can reflect the quality and safety of the samples to be used in clinical trials and/or the samples on the market.

The test substance should indicate the name, source, batch number, content (or specification), storage conditions, expiry date and preparation method, etc., and provide a quality inspection report.

Macromolecular drugs: The test substance should be a sample that can fully represent the quality and safety of the sample to be used in clinical trials and/or the marketed sample.

The process should be prepared after the process route and key process parameters are determined. Generally, it should be a sample of a pilot scale or above, otherwise there should be sufficient reasons.

The name, source, batch number, content (or specification), storage conditions, expiration date and preparation method of the test substance should be indicated, and a quality inspection report should be provided.

Traditional Chinese medicine and natural medicine: Due to the particularity of traditional Chinese medicine, it is recommended to use it now, otherwise data should be provided to support the quality stability and uniformity of the test substance after preparation.

When the administration time is longer, it should be investigated whether the volume after preparation will swell with the prolonged storage time and cause the final concentration to be inaccurate. If the volume or method of administration is limited, the drug substance can be used for testing.

The drug delivery formulations of macromolecular drugs and small molecule drugs are very different in the choice of solvents or excipients. Macromolecular drugs are mostly made into solutions for injection; small molecule drugs have various properties, and can be made into solutions or made according to their properties. Suspensions and emulsions are used for oral administration.

The solvents and/or auxiliary materials used should be marked with the name, standard, batch number, expiration date, specifications and production unit, etc., and meet the test requirements.

During the test, samples of the test substance administration preparation should be analyzed and an analysis report should be provided.

3. Dose selection

Dosage design should take into account the endpoints evaluated by the various tests conducted before, the physical and chemical properties and bioavailability of the test substance, etc.; local administration should ensure sufficient contact time.

In principle, at least three dose groups of low, medium and high doses should be set up for repeated administration of TK test, as well as a vehicle (or excipient) control group. If necessary, a blank control group and/or a positive control group should be set up.

In principle, high doses can cause the animals to be fully exposed to produce obvious toxic reactions, or reach the maximum feasible dose (MFD), or the system exposure can reach 50 times the clinical system exposure (based on AUC).

In principle, the low dose is equivalent to or higher than the animal effective dose or the equivalent dose for clinical use.

The middle dose should be established between the high dose and the low dose to investigate the dose-response relationship of toxicity.

If it is necessary to change the dose in the middle of the test, the reason for the dose adjustment should be explained and the dose adjustment process should be fully recorded.

4. Route of administration

Should be consistent with the proposed clinical approach, if inconsistent, the reasons should be explained.

In principle, in repeated administration toxicity tests, drugs with short half-life such as small molecule chemical drugs should be administered daily, and drugs with long half-life such as macromolecular monoclonal antibodies can be administered once a week.

The test substance can be designed according to the characteristics of the specific drug according to its toxicity characteristics and clinical dosing schedule.

There are many ways to administer small molecule drugs, including oral, intravenous, and inhalation. Because of poor intestinal absorption and/or gastric degradation of large molecule drugs such as proteins and peptides, the oral bioavailability is generally less than 1% ~ 2%, usually by subcutaneous administration, intramuscular injection, intravenous injection.

The maximum administration volume of various administration routes depends on the species of experimental animals and the nature of the preparation.

The general recommended dosing volume and maximum dosing volume are shown in Table 1.

The minimum administration volume for various administration routes depends on the solubility of the drug in the formulation and the minimum volume that can be accurately measured.

5. Sample collection

The prerequisite for collecting blood samples is that there is a dynamic equilibrium relationship between the exposure of the test substance in the plasma and the concentration of the target or toxicity target, and the test substance easily enters the system of animals and humans.

If the exposure of the test substance in the blood cannot reflect the toxic reaction of the target tissue or organ, it may be necessary to consider using urine, other body fluids, and target tissues or organs to determine the concentration of the test substance.

The time point of sample collection should try to reach the frequency required for exposure evaluation, but not too frequently, so as to avoid interference with the normal conduct of the toxicity test and cause excessive physiological stress in the animal.

Normally, TK data in the toxicity test of large animals is collected from the main research laboratory animal, and TK data in the toxicity test of rodents can be collected from the satellite group of laboratory animals for monitoring or characteristic research.

Monitor is to collect blood samples at 1 to 3 time points during the dosing interval to estimate Ctime or Cmax, often sampling at the beginning and end of dosing, single-dose toxicity dosing test or shorter-term repeated dosing Toxicity testing may consider carrying out exposure monitoring.

The profile is to collect blood samples at 4 to 8 time points between administrations to estimate Cmax and/or Ctime and AUC.

The calculation of the maximum limit of blood volume mainly relies on accurate data on circulating blood volume.

The total amount of blood depends on the species, gender, age, health and nutritional status. Under normal circumstances, the total circulating blood volume is 55 to 77 mL·kg-1, see Table 2.

When a single blood collection (toxicology study) does not exceed 15% of the total blood volume of the animal, the blood collection can be repeated after 3 to 4 weeks.

Long-term multiple blood sampling (such as the TK study) does not exceed 10% of the total blood volume every 24 hours, and can recover after 1 to 2 weeks.

Too much collection and/or blood collection can cause anemia. Changes in hematological indicators in toxicology experiments are very important. Multiple blood sampling will affect these indicators. Special attention should be paid to the recovery time after multiple blood sampling.

A large amount of blood (such as 20%) during TK research will cause hemodynamic changes, which may affect parameters such as half-life.

In terms of blood collection methods, we must also take into account animal welfare.

After collecting whole blood, for small molecule drugs, more plasma samples are prepared for TK research. This is because the proportion of most small molecule drugs into red blood cells is extremely low; for large molecule drugs, plasma or serum samples can be prepared for TK For research, serum is generally recommended because the background value of serum is lower.

3 Analysis and determination

1. There is a good correlation between the systemic exposure of the test substance and the toxic reaction

Generally, the correlation between the pharmacological effects of the test substance and the concentration of the test substance at the site of action is better than its correlation with the administered dose.

Similarly, the toxicity of the test substance has a good correlation with the concentration of the test substance in a specific toxic target organ or tissue.

If the test substance is highly permeable at the target site, the concentration of the test substance in the site should be in a dynamic balance and a certain ratio relationship with the concentration of the test substance in the blood. The concentration of the test substance in the plasma or blood can be used to reflect Exposure of the test substance at the target site.

2. The system exposure of the test substance lacks a good correlation with the toxic reaction

In this case, careful analysis should be performed. Generally, there are two situations: ① The selected analyte is incorrect, which is not the material basis for the toxic reaction.

② The changes between the systemic exposure of the whole body and the exposure of toxic target organs or organs are not parallel.

At this time, it is necessary to measure the exposure of the target site to evaluate its toxicity or use a mathematical model to reveal the relationship between the systemic exposure and the exposure of the toxic target organ, and use this relationship to indirectly reflect the relationship between the systemic exposure and the toxicity. relationship.

3. Metabolite exposure assessment

The situations that need to pay attention to the concentration of metabolites in plasma or body fluids in exposure assessment are as follows: ① The test substance is a “precursor compound” and the metabolites converted from it are the main active ingredients.

② The test substance can be metabolized into one or more metabolites with pharmacological or toxicological activity, and the metabolites can cause obvious tissue/organ reactions.

③ The test substance is extensively metabolized in the body, and the toxicity test can only be used to assess the exposure by measuring the metabolite concentration in plasma or tissue.

4. Bioanalytical methods

The analysis methods of drugs and metabolites in biological samples include chromatography, ligent binding assay (LBA), and radioisotope labeling.

The determination method with good specificity and high sensitivity should be selected according to the nature of the test substance.

In general, chromatographic methods are often used for chemical medicines, traditional Chinese medicines, and natural medicines, including high performance liquid chromatography (HPLC), gas chromatography (GC) and chromatography-mass spectrometry (LC-MS, LC-MS/MS, GC-MS, GC-MS /MS); Macromolecular drugs are mostly determined by immunological methods of ligand binding analysis.

Before the TK research and determination work is carried out, the verification of the analytical method of the analyte in the biological matrix (biological fluid or tissue) should be completed, and the detection limit should meet the expected concentration range during the TK research, and the metabolism and species differences should be considered.

Chromatographic biochemical sample analysis method verification includes investigating method selectivity, residue, standard curve, accuracy and precision, matrix effect, recovery rate, lower limit of quantification, upper limit of quantification, dilution reliability and stability.

The method for analyzing immunobiological samples should also examine the method’s matrix minimum required dilution, specificity, dilution linearity, and parallelism.

EMA took effect in 2012 to implement the guidelines for the verification of biological sample analysis methods, and released a revised version in 2014.

The US FDA issued new guidelines for the verification of biological sample analysis methods in 2013.

The 2015 edition of the Chinese Pharmacopoeia of the People’s Republic of my country also promulgated guidelines for the verification of quantitative analysis methods for biological samples.

When measuring TK samples, an analysis batch includes blank samples, zero-concentration samples, calibration standard curve samples with at least 6 concentration levels, at least 3 double QC samples with concentration levels or QC samples with 5% test sample amount, and the analyzed TK sample.

The processing methods of TK samples, quality control samples and standard curve samples are the same as those during method verification to ensure that the analysis batch is acceptable.

It is best to measure TK samples from the same individual in the same batch.

The quality control samples are dispersed throughout the analysis batch to ensure the accuracy and precision of the entire analysis batch.

The deviation of at least 5 effective concentration standard curve samples in the standard curve is within ± 15% (± 20%, LBA), the deviation of the lower limit of quantification standard curve sample is within ± 20% (± 25%, LBA), the correlation coefficient r2≥ 0.990 0; If a standard curve sample does not meet the standard, you can delete the data of the standard curve sample, use the remaining standard curve samples to recalculate, and perform regression analysis.

The accuracy deviation of the quality control samples should be within ± 15% (± 20%, LBA) of the labeled concentration. At least 67% of the quality control samples and at least 50% of the quality control samples at each concentration level should meet this standard; If these standards are not met, the analysis batch should be rejected, and the corresponding TK plasma samples should be re-extracted and analyzed; the average accuracy and precision between batches of all accepted analysis batches should also be within ± 15% (± 20%, LBA ), otherwise additional investigation is required to explain the reason for the deviation.

Reanalyze the TK samples in another analysis batch on a different day, and carry out incurred sample reanalysis (ISR) to evaluate the accuracy of the actual sample measurement.

Re-analyze 10% TK samples, including samples near Cmax and the elimination phase.

For repeated tests of at least 67% of the quality control samples, the difference between the concentration measured by the original analysis and the concentration measured by the reanalysis should be within ± 20% (± 30%, LBA) of the average of the two.

Samples with a concentration higher than the upper limit of quantification should be diluted with the corresponding blank matrix and re-measured.

For samples with a concentration lower than the lower limit of quantification, during TK analysis, samples taken before reaching Cmax should be calculated as zero, and samples taken after reaching Cmax should be calculated as not detectable (ND) to reduce The effect of zero value on AUC calculation.

4 Invention project

1. Time history research

Calculate the TK parameter by measuring the TK sample concentration at the appropriate time point. The degree of exposure can be expressed by the plasma (serum or whole blood) concentration or AUC of the prototype compound and/or its metabolites.

In some cases, you should choose to determine the concentration of the test substance in the tissue. The evaluated TK parameters usually include AUC0 ~ t, Cmax and Ctime.

Pre-clinical TK studies generally choose non-compartmental analysis (NCA) to fit medication-time data and calculate kinetic parameters. See Table 3 for the difference and applicable scope of the two fitting methods of non-compartmental model and compartmental model.

Cmax and AUC are kinetic parameters describing the degree of drug exposure.

Cmax is the highest concentration measured in the biological matrix. AUC is the area under the curve of plasma drug concentration-time curve. It is used in the TK study to compare exposures between different doses and calculate the accumulation ratio of multiple administrations (especially drugs with long half-lives), AUC Plotting the dose to evaluate whether the drug is linear kinetics is used to evaluate whether the exposure is proportional to the dose.

2. Single-dose toxicity test accompanied by TK study

The results of the TK study of the single-dose toxicity test are helpful to evaluate and predict the choice of dosage form and the exposure rate and duration after administration, as well as the selection of appropriate dosage levels in subsequent studies.

For example, after a single intravenous bolus administration of 15.0 mg·kg-1 Perjeta injection (anti-HER2 humanized monoclonal antibody pertuzumab), in vivo characteristics study and TK parameter evaluation were carried out.

The exposure AUC of pertuzumab in cynomolgus monkeys (0 ~ 1 344 h) is (68 662.8 ±17 975.0) μg·h·mL-1, and Tmax is the first blood sampling time point 0.5 h after the bolus injection. t1 /2 is (232.0 ± 128.6) h, CL is (0.229 1 ± 0.062 7) mL·h-1·kg-1, and Vss is (62.46 ±16.27) mg·kg-1.

3. Repeated dosing toxicity test accompanied by TK study

The TK study includes regular exposure monitoring and characteristic studies from the first administration to the end of the administration.

When there are unexplainable toxicity problems in early toxicity tests, it may be necessary to extend or shorten the time for toxicity monitoring and characteristic studies of the test substance, or to revise the research content.

For example, the new class 1.1 drug PARP inhibitor A is rapidly absorbed and metabolized in healthy Beagle dogs after intragastric administration, and the blood concentration in the body is positively correlated with the dose. The peak concentration is reached about 0.43 h after administration, and it takes about 1.84 for 63% of the drug to be eliminated from the body. h.

There is no gender difference in drug concentration in the body. The exposure in Beagle dogs is positively correlated with the dose.

The body exposure of repeated doses of 1, 3, and 6 mg·kg-1 for 3 months was linear, and the proportion of the increase in the exposure and the increase in the dose was consistent, and there was no significant accumulation.

4. Genotoxicity test accompanied by TK research

When the result of the in vivo genotoxicity test is negative, the risk of genotoxicity should be assessed in conjunction with the exposure data.

Measure the exposure of the test substance and/or its metabolites in blood or plasma, or directly measure the exposure of the test substance and/or its metabolites in the target tissue for evaluation.

5. Reproductive toxicity test accompanied by TK study

The TK study helps to determine whether the different doses at different stages in the reproductive toxicity test have achieved sufficient exposure, but the possible differences in the dynamic characteristics of animals during pregnancy and non-pregnancy should be considered.

The TK data should also include fetal/pup data to evaluate whether the test substance and/or metabolite can pass through the placental barrier and/or milk secretion.

6. Carcinogenicity test accompanied by TK research

The appropriate maximum dose in the carcinogenicity test should be determined based on the possible systemic exposure of the tested animals and humans.

The dose selected in the carcinogenicity test should produce a systemic exposure that exceeds the exposure at the maximum therapeutic dose for humans several times.

Monitoring is used to ensure that the exposure in the main study is consistent with the kinetic characterization obtained in an independent or specific dose exploration study.

For example, a PEGylated polypeptide is planned to carry out a 24 months long-term carcinogenicity experiment for rats by subcutaneous injection. In order to confirm the feasibility of the dose and frequency of the carcinogenic experiment, the pre-experimental accompanied TK study was carried out to observe 2 doses They were administered once every 4 d, 5 times in total, and once every 7 d. The exposure changes after a total of 3 administrations, and the number of administrations required to reach a steady state.

The results showed that the blood drug concentration in the body did not reach a steady state after the latter dosing regimen after 3 consecutive administrations; the former regimen reached a steady state after 3 consecutive administrations of high doses, and reached a steady state after 5 consecutive administrations of low doses. state.

It was finally determined to repeat the administration at 4 d intervals.

5 TK research outlook

1. Guiding Principles

In January 2016, the ICH expert group began to draft the ICH S3A Questions and Answers (Q&As) and formulated a detailed timetable. It is expected that the guidelines will be promulgated and effective on April 30, 2017.

The Organisation for Economic Co-operation and Development (OECD) issued a draft of the TK guidelines in 2008 and issued them in 2008, which took effect on July 22, 2010. The guidelines are similar to experimental guidelines. Fully use rats to carry out TK research.

The guidelines for cosmetic TK issued by the OECD in 2010 are to completely use alternative methods, that is, non-animal in vitro methods for evaluation.

2. TK parameters

Clearance (Clearance, CL) is an important parameter that characterizes drug elimination. Small molecule drugs are mostly cleared in the liver and kidneys, while macromolecular drugs are more diverse and will be cleared in the blood, liver, kidney, injection site and receptor-mediated.

If the toxicity test results in organ pathological changes, it will affect the organ-specific clearance rate, thereby affecting the total clearance rate and changing the body exposure.

For drugs with linear kinetic characteristics, the biological half-life (half-life, t1/2) is a characteristic parameter of the drug, and it does not change due to the drug formulation or administration method (dose, route).

But the most accurate biological half-life is calculated after intravenous administration. The apparent biological half-life (apparent t1/2) obtained by oral or extravascular administration will be different from the biological half-life of intravenous administration.

Generally speaking, the apparent t1/2 of oral administration of small molecule drugs is longer than that of intravenous administration, and the t1/2 of subcutaneous administration of monoclonal antibodies is almost the same as that of intravenous administration.

Biological half-life can be used as an indicator to reflect the changes in the elimination of drugs in the body in the study of toxicity test TK.

When the toxicity test increases the dose and repeated administration results in a non-linear change in drug elimination, t 1/2 will increase and AUC will increase disproportionately.

According to the formula t1 /2 = 0.693 /λz, λz is the elimination rate constant, which can be calculated by the slope of the end division phase of the semi-logarithmic diagram of blood concentration versus time, so the determination of the true end elimination phase is very important.

The pharmacokinetic software uses linear fitting to eliminate phase points to calculate λz, and the fitted r2 value can be used as an inspection index. When r2<0.8, the parameters related to λz are t1 /2, Vd and AUC0 ~ ∞ reliability reduce. Therefore, the value of r2 should be reported.

AUC0 ~ ∞ is derived from the sum of AUC0 ~ t and AUCTlast - ∞, and AUCTlast ~ ∞ is extrapolated. It is generally believed that if AUCTlast ~ ∞ means AUC% extrapolated > 20% ~ 25%, it indicates that AUC0 ~∞ will exist. Obviously wrong estimates, other parameters related to AUC0 ~ ∞ such as CL and Vss may also have wrong estimates. Therefore, the AUC% extrapolated value should be reported.

3. Research Project

Through in vivo, in vitro, physiologically based toxicokinetic (PBTK) model construction, preclinical pharmacokinetics/pharmacodynamics (pharmacokinetics/pharmacodynamics, PK/PD) correlation and other research methods, try to reveal the test substance Dynamic changes in the body, elucidate the process and characteristics of drug absorption, bioavailability, target organs and toxic organs and other tissue distribution and tissue dynamics, biotransformation and metabolic enzyme induction/inhibition, fecal and urine bile excretion, and material balance.

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