Abstract EN:

Topotecan (Hycamtin®) is a topoisomerase I inhibitor cytotoxic agent. A rather large pharmacokinetic (PK) variability and demonstrated relationships between hematological toxicity and PK parameters are arguments for an optimisation of the treatment. In our work are reported the results of a phase I clinical study which allowed to demonstrate the potential interest of a more protracted administration schedule for topotecan and the feasibility of exploring an increasing number of administrations based on a daily fixed AUC rather than on a mg/m² dosing. A population analysis (NONMEM) allowed to obtain the PK parameters of I. V. And oral topotecan, as well as the associated variabilities, to explore the influence of covariates, and to propose a limited sampling strategy. A semi-physiological PK-PD model was used to modelise and describe the time course of topotecan-associated neutropenia, allowing to quantify the pharmacodynamic (toxicity) variability and to study the impact of covariates.