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Pharmacocinétique et pharmacogénétique du tamoxifène et du létrozole chez les patientes atteintes d’un cancer du sein hormonodépendant

Abstract : Tamoxifen and aromatase inhibitors are the main therapeutic options for adjuvant treatment of hormone-dependent breast cancer. High inter-individual variability of efficacy and toxicity of these drugs is observed which may be related to the variability of plasma drug concentrations. In the case of tamoxifen, its pharmacological activity depends on the formation of active metabolites, mainly endoxifen, via the cytochromes P450 (CYP2D6, CYP3A4/5, CYP2C9, CYP2C19). Concerning letrozole, it is metabolised via the CYP2A6 and CYP3A4 isoenzymes. The variable activity of CYP, due to genetic polymorphisms or concomitant use of CYP inhibitors or inducers, may impact the plasma exposure to the active compounds and in fine, the efficacy and toxicity of the treatment. The pharmacokinetic-pharmacogenetic analyses of the data from first follow-up visit in the PHACS study (prospective, multicenter, national, 2000 patients, 6 follow-up visits during 3 years) demonstrated the impact of CYP2D6 phenotype, CYP3A4*22, CYP2C19*2, and CYP2B6*6 genotypes and of the concomitant use of CYP2D6 inhibitors on tamoxifen metabolism. The longitudinal pharmacokinetic data for tamoxifen and its metabolites (6 to 36 months follow-up visits) were analysed simultaneously using non-linear mixed effects modelling (population approach). A joint pharmacokinetic model for tamoxifen and six metabolites was developed and validated. The significant covariates in the final model were: CYP2D6 phenotype, CYP3A4*22 and CYP2B6*6 genotypes, CYP2D6 inhibitors, age and body weight. Simulations of alternative dosing regimens were performed to propose an individualised dose of tamoxifen for patients at risk of subtherapeutic exposure to endoxifen. The pharmacokinetic-pharmacogenetic data for letrozole were analysed using the population approach. A one-compartment model was developed and validated. CYP2A6 activity was significantly associated with letrozole clearance. The model was used for identification of non-adherent patients based on their steady-state plasma concentrations.
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Alicja Puszkiel. Pharmacocinétique et pharmacogénétique du tamoxifène et du létrozole chez les patientes atteintes d’un cancer du sein hormonodépendant. Pharmacologie. Université Paul Sabatier - Toulouse III, 2019. Français. ⟨NNT : 2019TOU30250⟩. ⟨tel-03169403⟩

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