Chapter 23: Toxicokinetics

Plasma concentration analysis of samples from toxicology studies is now a routine part of safety assessment. The measurement and interpretation of this data is termed toxicokinetics. The measured concentrations allow interpretation of dose response within a study. Due to the processes of dissolution, absorption and metabolism and excretion plasma concentrations may not be linear with dose, resulting in shallow or exaggerated dose–response curves. To a much lesser degree of precision the measured concentrations allow comparison across species of pharmacological and toxicological effects, by correcting for pharmacokinetic differences. These pharmacokinetic/pharmacodynamic (PK/PD) cross-species comparisons allow some definition of the possible therapeutic windows in humans. Comparisons are best made using unbound drug concentrations, but investigators must be mindful of species differences in drug receptors, ion channels and enzymes which may be more influential than pharmacokinetic differences. Since the formalisation of toxicokinetic studies, the maximum plasma concentration (C_max) and the area under the plasma concentration curve (AUC) have been used as chief summary descriptors. Average plasma concentrations over the measured time course (C_av) have many advantages over AUC in advancing PK/PD interpretation of toxicology studies.