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Tamoxifen pharmacokinetics and pharmacogenetics in endocrine sensitive breast cancer patients

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Defense Thèse de doctorat : Univ. Genève, 2013 - Sc. 4617 - 2013/11/26
Abstract 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.
Keywords Population pharmacokineticsPharmacogeneticsTamoxifenEndoxifen4-hydroxy-tamoxifenN-desmethyl-tamoxifenLiquid chromatographyMass spectrometry.
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URN: urn:nbn:ch:unige-334293
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DAHMANE, Elyes Ben Ali. Tamoxifen pharmacokinetics and pharmacogenetics in endocrine sensitive breast cancer patients. Université de Genève. Thèse, 2013. https://archive-ouverte.unige.ch/unige:33429

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Deposited on : 2014-01-20

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