F. Fiorentini (2), M. Simeoni (1), I. Poggesi (2), G. Westerberg (2), M. Rocchetti (2)
(1) Dipartimento di Informatica e Sistemistica, Pavia University, Pavia, Italy. (2) Global Drug Metabolism, Pharmacia, Nerviano, Italy
Usually, pharmacokinetic information is obtained from satellite groups of animals during toxicological studies. This approach provides a characterization of the toxicological findings only in relation to the average estimates of the systemic exposure (typically Cmax, tmax, AUCs) in the satellite groups. In this way, the individual toxicological observations remain difficult to interpret in absence of a direct comparison with the exposure of the main study animals. A sparse sampling design together with a population analysis could however allow merging the individual toxicological observations with the corresponding estimate of the systemic exposure in the same animal. This allows a considerable expansion of the degree of information obtainable from the toxico-pharmacokinetic profile of the compound and, in addition, could provide reduction of costs in the subsequent phases of development.
An example of a real application of this kind of approach is provided here. Three typical studies that constitutes part of a toxicological program of a new intravenous anticancer drug were considered: an acute study after single administration, a short term study (7 days repeated administration) and a cyclic dose study. The data were analysed by using a 2-compartment model with elimination from the central compartment and a model of errors including random effects and fixed effects for gender, dose and cycle. The results compared with those obtained with more traditional approaches confirmed the adding value of the population analysis.
Reference: PAGE 13 (2004) Abstr 496 [www.page-meeting.org/?abstract=496]
Poster: poster