Purpose and Guidelines for Toxicokinetic Studies within the National Toxicology Program

Toxicokinetics (TK) is generation of kinetic data for systemic exposure and toxicity assessment of the drug. These studies help us to estimate the observed toxicity to that dose. TK evaluation is very important in drug development phase in both regulatory and scientific perspective. There are several guidelines to conduct TK study in animals recommended by regulatory bodies (OECD). TK evaluation is useful in selection of dose, dosing form, alternative dosing route, evaluation of toxicological mechanism, and also used for the setting safe dose level in clinical phases. This TK studies also used to reduces the animal number (replacement, reduction and refinement). On the other hand, TK data are practically used for the purpose of drug discovery such as lead-optimization and candidate-selection. Email:marketing@medicilon.com.cn Web:www.medicilon.com

The purpose of National Toxicology Program (NTP) toxicology/carcinogenicity studies is to identify toxic/carcinogenic effects resulting from exposure to a particular chemical or agent and to characterize dose-response relationships. In support of the toxicology/carcinogenicity studies, toxicokinetic (TK) studies are conducted to characterize the absorption, distribution, metabolism, and elimination (ADME) of xenobiotic materials and to quantify the influence of exposure on those properties. Toxicokinetic studies are proposed to * help in the design (e.g., dose selection, route of exposure, etc.) of meaningful and useful toxicology studies; * aid in the interpretation of toxicology studies by increasing our understanding of relationships between exposure, time-dependent target organ dosimetry, and adverse effects; and * define the parameters of dose, distribution, metabolism, and elimination that can be used in human risk assessment. Toxicokinetic studies also investigate the effects of sex, species, and age on ADME. Data collected during a toxicokinetic study focus on time profiles of parent chemical and metabolite concentrations in plasma and other tissues and can include rates of chemical absorption, metabolism, and excretion, chemical related changes in blood chemistry, bioavailability, protein binding, and depletion of cofactors. Ultimately, the data gathered during toxicology/carcinogenicity studies are used to estimate the risk to human health from exposure to a chemical. Characterization of relationships between toxic/carcinogenic endpoints and target organ dosimetry aid in the estimation of human risk. A description of a study design well-suited to the support of human risk assessment follows. This comprehensive design aims to collect the data necessary to develop physiologically based pharmacokinetic (PBPK) models incorporating some degree of anatomical realism and including all relevant biochemical and physiological processes. Prior to the determination of toxicological effects, it is impossible to propose a TK study design that is sufficient for all chemicals. The design proposed below contains elements believed to be necessary for the construction of PBPK models. The relative importance of some measurements may change depending on the compound under study. Two of the most difficult but critical problems in risk assessment are defining equivalent human dose and delineating the dose-response curve in the low-dose region. These problems motivate the recommendations to collect data to support the development and validation of PBPK models. If the only information available to the risk assessor is the applied or extemal dose, the estimated human equivalency dose will be based on several assumptions, such as equivalent absorption in laboratory animals and humans. However, uncertainties may exist in the predicted low-dose effects in humans if all of the doses that caused the adverse effect in the animal model occurred above the metabolic saturation exposure, if the chemical is absorbed differently in animals than in humans, or if the chemical is metabolized differently (qualitatively or quantitatively) between species. An objective of toxicokinetic studies is to improve our understanding of the relationship between external exposure and the tissue level of the toxic agent at the target site. By increasing our understanding of the relationships between target organ dosimetry and adverse effects, confidence in low-dose extrapolations of risk to humans is increased. Thus, knowledge of internal dose and factors that influence absorption, distribution, metabolism, and elimination in experimental animals and humans provide a greater scientific rationale for estimating low-dose risk than do estimates that are based solely on external exposure. Exposure- and time-dependent changes in target tissue concentrations of a parent compound and metabolites (especially if the adverse affects of exposure are due to particular metabolites) provide an even stronger scientific foundation for estimating equivalent human dose in various risk assessment models. Toxicokinetic/pharmacokinetic models provide the basis for more accurate low-dose extrapolations to humans. PBPK models can be adapted to different routes of exposure and dosage regimens and can accommodate factors that contribute to interindividual variabilities. Thus, the modeler can also provide valuable information relevant to the distribution of risk in exposed populations. The combination of dosimetry models with mechanistic data (e.g., mutagenicity, altered gene expression) can lead to more realistic biological models that would be useful in predicting site-specific dose responses and assessing human risk.