Concomitant Toxicokinetics: Techniques for and Interpretation of Exposure Data Obtained During the Conduct of Toxicology Studies

Abstract

Toxicokinetic analyses have become a routine component of preclinical toxicology studies with pharmaceutical candidates. Evaluation of plasma and/or tissue samples from animals used in toxicology studies (or concurrent satellite groups) provides information on dose proportionality, the potential for dose accumulation, and the sex and species differences in distribution and elimination. Toxicokinetic information is used by toxicologists, toxicology management, clinicians, institutional review boards, and regulatory agencies to ensure that exposure has occurred in animal species to a sufficient extent to minimize the potential risk of toxicities in humans. The requirements for descriptive toxicokinetics change depending on the stage of development of new drug candidates. Early in development, documentation of exposure in 1 species and sex of laboratory animal might be enough to justify preliminary development costs and initiation of product development. Later in development, it becomes necessary to know how new drug candidates are distributed and eliminated following subchronic and chronic administration in multiple species and both sexes. Finally, knowledge of toxicokinetics is used to help establish doses in long-term oncogenicity studies. Scientific, public, and regulatory pressures have recently dictated that the number of animals used in toxicology studies be closely monitored and minimized. Toxicokinetic evaluation of new drug candidates by a staggered sampling design is now routinely performed in our laboratories to maximize information obtained while reducing animal use.