A Pharmacokinetic‐Pharmacodynamic Model for Predicting Tumour Growth Inhibition in Mice: A Useful Tool in Oncology Drug Development

Abstract

The in vivo evaluation of the antitumour effect using xenografted mice is a fundamental step in the preclinical development process of oncology drugs. In this type of experiments tumour cells from immortalized human cell lines are inoculated in athymic mice; the animals are then randomized in groups treated either with a vehicle or an active treatment and the corresponding tumour growth curves are compared for obtaining information on the efficacy of tested compounds. In this respect, one of the most usual metrics is the tumour growth inhibition. Tumour growth inhibition is calculated as difference between tumour weight in treated and control animals expressed as percentage of tumour weight in control animals. However, this metric is doseand schedule-dependent and may be strongly influenced by the time-point at which the measurements are performed. We recently developed a simple and effective pharmacokinetic-pharmacodynamic model linking the plasma concentrations of anticancer compounds to the effect on the tumour growth (Simeoni et al. 2004). The model successfully described the growth of total tumour mass obtained in mice given anticancer drugs, providing physiologically relevant parameters. In this communication two examples of its application to a discovery candidate and to a known anticancer drug are shown. The dependencies of tumour growth inhibition on the experimental conditions are also discussed using simulations. The experiments performed using A2780 human ovarian carcinoma cell lines were implanted sub cute into the left flank of nude mice (nΩ6–10/group). At palpable tumour, mice received placebo or the active drug (Drug A or vinblastine). Tumour dimensions were measured by caliper and tumour weights were calculated, assuming unit density, as D i d2/2, where D and d are the larger and the smaller di-