Abstract

The current work integrates cell-cycle dynamics occurring in the bone marrow compartment as a key element in the structure of a semi-mechanistic pharmacokinetic/pharmacodynamic(PK/PD) model for neutropenic effects,aiming to describe with the same set of system and drug related parameters, longitudinal data of neutropenia gathered after the administration of the anticancer drug diflomotecan (9,10-difluoro-homocamptothecin) under different dosing schedules to patients (n=111) with advanced solid tumours. To achieve such objective thegeneral framework of the neutropenia models was expanded including one additional physiological process resembling cell cycle dynamics. The main assumptions of the proposed model are: (i) within the stem cell compartment proliferative and quiescent cells coexist and (ii & iii) only cells in the proliferative condition are sensitive to drug effects, and capable to follow the maturation chain.Cell cycle dynamics were characterized by the following two new parameters, FProl, and kcycle, the first accounting for the fraction of proliferative cells that enter into the maturation chain, and the latter quantifying the dynamic of the transit between the different cells status. Both model parameters resulted identifiable as indicated by the results from a bootstrap analysis, and their estimates were supported by literature data. The estimates of FProl and kcycle were 0.58 and 1.94 day-1, respectively. The new model could describe properly the neutropenic effects of diflomotecan after very different dosing scenarios, and can be used to explore the potential impact of dosing schedule dependencies on neutropenia prediction.