Evaluation du suivi thérapeutique pharmacologique du carboplatine et étude pharmacocinétique-pharmacogénétique de l'étoposide dans le cadre d'un essai clinique de phase II d'intensification thérapeutique en cancérologie

Abstract : The TI-CE protocol ((Taxol, Ifosfamide, Carboplatin and Etoposide) is the standard treatment of germ cell tumor refractory to first-line chemotherapy or relapsed germ cell tumor having unfavorable prognostic features. A phase II study was conducted and consisted in adapting the dose of (high dose) carboplatin using therapeutic drug monitoring (TDM) of unbound concentrations instead of the usual method of dose individualization based on a target area under the curve (AUC) of unbound concentrations and predicted unbound clearance. Pharmacokinetic analyses carried out in the context of this thesis have demonstrated the feasibility of conducting the TDM as well as its performance in terms of controlling the variability of AUC of carboplatin in the TI-CE protocol. However, the use of this practice is limited, in some hospitals, by material and human constraints related to the ultrafiltration of plasma samples to obtain unbound concentrations. A method was developed and validated to enable the use of total plasma concentrations for the TDM instead of unbound concentrations. Furthermore, the pharmacokinetic study of etoposide, used in combination with carboplatin during the dose intensification phase of the protocol, showed that the usual dose calculation method based on body surface area is associated with a low interindividual variability of exposure and that TDM is, therefore, not necessary for this drug. Finally, the role of different genetic factors in the ototoxicity of carboplatin and in the pharmacology of etoposide was also assessed. In conclusion, these analyses help to improve the level of care of patients treated with this protocol of high dose carboplatin and etoposide as well as our current knowledge of these two important cytotoxic drugs.
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Sotheara Moeung. Evaluation du suivi thérapeutique pharmacologique du carboplatine et étude pharmacocinétique-pharmacogénétique de l'étoposide dans le cadre d'un essai clinique de phase II d'intensification thérapeutique en cancérologie. Pharmacologie. Université Paul Sabatier - Toulouse III, 2018. Français. ⟨NNT : 2018TOU30146⟩. ⟨tel-02301589⟩

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