Toxicokinetics in preclinical drug development of small‐molecule new chemical entities

Toxicokinetics (TK) is an integral part of nonclinical (preclinical) safety assessment of small-molecule new chemical entities in drug development. It is employed to describe the systemic exposure of a drug candidate and/or its important metabolite(s) achieved in study animals and elucidate the relationship (proportional, over-proportional, or under-proportional) between systemic exposure and dose administered and the associated differences/similarities between male and female animals along with the possible accumulation/induction. TK data and the derived parameters are employed to propose safe starting doses for clinical use of the new drug candidate through proper extrapolation of findings in study animals to humans. This review has attempted to highlight the health authority expectations on TK assessment in supporting preclinical safety profiling of new chemical entities. A robust TK assessment requires good understanding of absorption, distribution, metabolism, and elimination processes of drug candidate, adequate TK sampling (e.g., controls where relevant), implementation of fit-for-purpose bioanalytical methods (validated or scientifically qualified) along with necessary measures to prevent mis-dosing or ex vivo contamination, and establishment of stability of the drug candidate and/or its metabolite(s) in the intended species matrix to ensure the reliability of bioanalytical and TK data. The latter provides a vital link between animal experiments and human safety.