Systems Toxicology Modeling for Prediction in Humans

Abstract

This chapter aims to illustrate the ability of physiologically based mechanistic mathematical models to predict pharmacokinetics and toxicity across species. The underlying principle is that toxicity must be interpreted in the physiological context where it is measured. Various methodologies for predicting the pharmacokinetics, QT prolongation and proarrhythmic risk are evaluated. Finally an integration of both pharmacokinetics and toxicokinetics in chemotherapy-induced neutropenia is discussed. It is believed that the methodologies presented for integrating available knowledge across experiments to predict toxicology in humans will ultimately make drug development more efficient, cost cost-effective, and socially more acceptable. Keywords: pharmacokinetics; PBPK; toxicokinetics; QT prolongation; cardiac; electrophysiology; myelosuppression; neutropenia