Tamoxifen pharmacokinetics and pharmacogenetics in endocrine sensitive breast cancer patients

Diplôme Thèse Tamoxifen pharmacokinetics and pharmacogenetics in endocrine sensitive breast cancer patients eng 2013-11-26 author Dahmane Elyes Ben Ali 643946 director Csajka Chantal 657943 director Decosterd Laurent 826211 10.13097/archive-ouverte/unige:33429 urn:nbn:ch:unige-334293 Sc. 4617 Tamoxifen is used for the treatment of estrogen-sensitive breast cancer. It is a prodrug that is bioactivated into endoxifen, the active metabolite mostly responsible for tamoxifen efficacy. Endoxifen levels show large inter-individual variability. Cytochrome (CYP)2D6 activity was presumed to play a role in predicting this variability and treatment efficacy. The objectives of the thesis were to assess the influence of pharmacogenetic and non-genetic factors on this variability and study the tamoxifen/endoxifen dose-concentration relationship. Based on a population pharmacokinetic study, we confirmed that CYP2D6 phenotype and inhibitors were major factors affecting endoxifen levels. We demonstrated the effectiveness of doubling tamoxifen dose in correcting low endoxifen levels, except for CYP2D6 poor metabolizers or patients under potent CYP2D6 inhibitors. We showed that CYP2D6 phenotype is a modest predictor of endoxifen exposure and demonstrated the rational of endoxifen concentration monitoring for detecting patients at risk of suboptimal treatment and for guiding tamoxifen dosage optimization. Population pharmacokinetics Pharmacogenetics Tamoxifen Endoxifen 4-hydroxy-tamoxifen N-desmethyl-tamoxifen Liquid chromatography Mass spectrometry Dewey 615 31 Section des sciences pharmaceutiques 17 false ce0cea2b-a520-439b-8a2e-ec9b68a50dc7 Thesis Public Thesis.pdf 11598386 application/pdf Private 2015-01-17 a64a0e79e8c9616be5f3c67011b6cc4135743db519de16d7450b500482339fdc openAccess Faculté des sciences / Section des sciences pharmaceutiques

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Tamoxifen pharmacokinetics and pharmacogenetics in endocrine sensitive breast cancer patients				2013	1,548	1,426

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Dahmane, Elyes Ben Ali