Evaluating the Influence of Different Sources of Variability in the PK/PD Tumor Growth Inhibition (TGI) Model
F. Del Bene (1), M. Germani (1), F. Fiorentini (1), G. De Nicolao (2), P. Magni (2), M. Rocchetti (1)
(1) Pharmacokinetics & Modeling, Accelera - Nerviano Medical Sciences, Italy; (2) Dipartimento di Informatica e Sistemistica, Universitŗ di Pavia, Italy
Objectives: Generally, the estimate of the in vivo effect of anticancer compounds is based on the evaluation of the changes in the average tumor growth profiles in treated versus untreated group of 8-10 animals. We recently developed a simple and effective pharmacokinetic-pharmacodynamic model linking the plasma concentrations of anticancer compounds to the effect on the tumour growth . The model has been successfully applied to many different drugs and cell lines, showing also a good predictivity of the expected activity of the tested compounds in the clinics . Essentially, the model describes the system as the interaction of three major processes: the unperturbed tumor growth in untreated animals (representing the biological system), the action of the drug on the tumor growth (representing the pharmacological part of the system) and the pharmacokinetics (PK) of the tested compound. The aim of this communication is to explore and discuss the different sources of variability affecting the response of the system in terms of PD data.
Methods: Different sets of experimental data were considered. For each tested compound the inter-animal variability of the PK and the tumor growth PD parameters was estimated through the variance-covariance matrix of parameters derived from individual fittings. The influence of these different sources of variability was investigated analysing series of simulated tumor growth profiles and comparing them with the observed individual data.
Results and Conclusions: The Monte Carlo simulations based on the PK/PD model, through its parameters, allowed to identify and assess the contribution of the different processes to the overall behavior of the system. The simulated tumor growth profiles in treated animals indicate the biological process (represented by the parameters modeling unperturbed tumor growth) as the major factor influencing the variability of the system response. These analyses are expected to prove particularly useful for the subsequent development of a comprehensive population approach.
 Simeoni M, Magni P, Cammia C, De Nicolao G, Croci V, Pesenti E, Germani M, Poggesi I, Rocchetti M. Predictive pharmacokinetic-pharmacodynamic modeling of tumor growth kinetics in xenograft models after administrations of anticancer agents. Cancer Research. 2004, 64: 1094-1101.
 Rocchetti M, Simeoni M, Pesenti E, De Nicolao G, Poggesi I. Predicting the active doses in humans from animal studies: a novel approach in oncology. European Journal of Cancer, 43, 1862,1868, 2007.