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RESEARCH PRODUCT

A modelling population-based approach to the effect of granulocyte growth factors during chemotherapy-induced neutropenia

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The work of this thesis is based on results of a cohort study whose main objective was to define the optimal schedule of prophylactic administration of granulocyte growth factors (G-CSF) in the context of FOLFIRINOX treatment. For this purpose, a pharmacokinetic/pharmacodynamic (PK/PD) model was built to describe the absolute neutrophil counts (ANC) time course in our population, including the three chemotherapies neutropenic effect, but also the stimulating effect of exogenous G-CSF on the proliferation and maturation of neutrophils. Based on the estimates of the model parameters, simulations were performed to determine the incidence and duration of neutropenia for each prophylactic G-CSF schedule depending on the begining, the duration but also the nature of the treatment (pegylated formulation or not). The pre-therapeutic ANC value was considered; in case of high initial ANC (> 6.5 G/L), the use of prophylactic treatment does not seems necessary due to the limited risk of neutropenia. Furthermore, for patients whose initial ANC is below 6.5 G/L, based on our results, a single administration of peg-G-CSF 24 hours after the end of the 46 hours 5-FU infusion seems to be the most appropriate prophylactic schedule to reduce the incidence and the duration of FOLFIRINOX-induced neutropenia. However, contrary to popular belief, increasing the number of daily G-CSF injections or late administration of G-CSF is not necessarily beneficial for patients due to the increased incidence of severe neutropenia compared to the absence of treatment.