Pharmacokinetics and Toxicity Testing

Abstract

The pharmacokinetic basis for the design of toxicity tests is discussed with reference to the absorption and clearance of drugs. The absorption and clearance of a wide range of drugs by laboratory animals and man has been examined and reviewed to provide a firm basis against which new drugs can be compared. Some pitfalls in either the empirical approach to toxicology or the incorrect interpretation of kinetic data are highlighted. An approach is outlined for the rational application of animal pharmacokinetic data in the assessment of the safety in man of a new therapeutic agent.

The Acquisition and Application of Absorption, Distribution, Metabolism, and Excretion (ADME) Data in Agricultural Chemical Safety Assessments

“…This requires establishing a baseline pharmacokinetic understanding. The objective of these baseline pharmacokinetic studies is to establish the extent and rate of absorption, bioavailability, the general distribution of the chemical, the extent of metabolism, and the routes and rates of excretion (Clark and Smith, 1984). These experiments will provide information on any nonlinear kinetics resulting from saturation of absorption, shifts in metabolic pathways, or routes of excretion.…”

“…Nevertheless, for many of these endpoints, the dose selection and the selection of the "most human-like test species" in the bioassay are based on considerations of pharmacokinetics and metabolism. Therefore, in contrast to pesticides, toxicokinetic data are used on a standard basis in drug development to assist in candidate selection, appropriate species selection for toxicity testing, and dose selection for toxicity studies, as well as in safety assessment, by comparing experimental animal versus human systemic exposure (Clark and Smith, 1984). International harmonization of guidelines on toxicokinetics and dose selection in toxicity studies for pharmaceuticals has been achieved, and those guidelines can be reviewed on the U.S. Food and Drug Administration (FDA) homepage (http://www.fda.gov/cder/guidance/index.htm).…”

Integration of animal pharmacokinetic and pharmacodynamic data in drug safety assessment

“…These effects were eventually rationalised by the steady-state concentration being at a 1:1 molar ratio of drug and albumin and elevations in this concentration caused markedly increased distrib-ution of the drug and resultant toxicity (16).…”

The Role of Pharmacokinetic Studies in Drug Discovery: Where are We Now, How Did We Get Here and Where are We Going?

“…PK studies in animals were routinely used by drug discovery projects before the development and validation of predictive in vitro tools. It is possible that the use of PK studies today is influenced by that legacy, and strategies have not fully evolved to reflect the power of predictive tools currently available [1,2].Although the fundamentals of what we would now recognize as pharmacokinetic theory and analysis were established by 1960 [3], it took another 20 years before PK studies started to become integral to the drug discovery process [4]. There were four keys steps that made PK optimization an achievable medicinal chemistry goal, thrusting drug metabolism and pharmacokinetics to the heart of discovery projects.…”

“…Although the fundamentals of what we would now recognize as pharmacokinetic theory and analysis were established by 1960 [3], it took another 20 years before PK studies started to become integral to the drug discovery process [4]. There were four keys steps that made PK optimization an achievable medicinal chemistry goal, thrusting drug metabolism and pharmacokinetics to the heart of discovery projects.…”