E. Dahmane (1) (2), K. Zaman (3), M. Galmiche (3), L. Perey (4), A. Bodmer (5), S. Leyvraz (3), C.Eap (6), L.Decosterd (1) (7), T. Buclin (1), C.Csajka (1) (2)
(1) Division of Clinical Pharmacology, Department of Laboratories, University Hospital Center and University of Lausanne; (2) School of Pharmacy, Department of Pharmaceutical Sciences, University of Geneva and Lausanne, Geneva, Switzerland; (3) Breast Center, Multidisciplinary Center for Oncology (CePO), University Hospital CHUV, Lausanne; (4) Medical Oncology, Hospital of Morges; (5) Medical Oncology, University Hospital Geneva, Switzerland; (6) Center for Psychiatric Neurosciences, University Hospital CHUV, Lausanne; (7) Innovation and Development Unit, Department of Laboratories, University Hospital Center and University of Lausanne, Switzerland
Objectives: Tamoxifen (Tam) treated patients with null or reduced CYP2D6 activity display low endoxifen exposure and thus might experience lower benefit from their treatment [1]. The objectives of the trial are to study Tam and its major metabolites concentrations and to evaluate the influence of doubling tamoxifen dose on endoxifen levels in the different CYP2D6 genotype groups. Correlations between endoxifen concentrations and both CYP2D6 genotype and phenotype were also explored.
Methods: Patients under tamoxifen 20mg once daily (QD) were prospectively genotyped and phenotyped (dextromethorphan/dextrorphan ratio test) for CYP2D6. Patients were categorized into 4 genotype groups: poor, intermediate and extensive metabolizers (PM/IM/EM) according to their CYP26 genotype. Plasma levels of Tam, N-desmethyltamoxifen (NDTam), 4-hydroxytamoxifen (4OHTam) Â and endoxifen were measured [2] at baseline (20mg QD), then at 30, 90 and 120 days after dose escalation to 20 mg twice daily. Â Plasma levels increase and between-group differences in endoxifen levels were tested using ANOVA. Correlations between CYP2D6 genotype/phenotype and endoxifen or endoxifen/NDTam levels ratio were performed using linear regression models.
Results: 63 patients were available for this analysis. At baseline, endoxifen levels (CV %) were lower in PMs: 7 ng/mL (36%) than in EMs: 24 ng/mL (71%) (P = 0.001), but not statistically different from the IMs: 16 ng/mL (70%) (P = 0.08). After doubling tamoxifen dose, endoxifen concentration increased less than 2 fold (P<0.0001) and to a similar extent in PMs, IMs and EMs with respectively, 1.5 (18%), 1.5 (28%) and 1.7 (30%) fold increase from baseline (P = 0.18). A modest correlation between CYP2D6 genotype groups and endoxifen levels (R-squared = 28%, P = 0.002) and endoxifen/NDTam levels ratio (43%, P < 0.0001) was observed. CYP2D6 phenotype explained 31% (P < 0.0001) of endoxifen levels variability and 60% (P < 0.0001) of endoxifen/NDTam levels ratio.
Conclusions: An important interindividual and intergroup variability in endoxifen levels was observed, which was best correlated to CYP2D6 phenotype. Endoxifen concentration monitoring would thus be beneficial for individualizing tamoxifen dose. In that purpose, a population pharmacokinetic modeling will be performed that will bring a better understanding of Tam and its metabolites disposition and variability, which would be useful for Tam dose optimization strategies.
References:
[1] Madlensky L, et al. Clin Pharmacol Ther. 2011 May;89(5):718-25.
[2] Dahmane E, et al. J Chromatogr B Analyt Technol Biomed Life Sci. 2010 Dec 15;878(32):3402-14.
Reference: PAGE 21 (2012) Abstr 2547 [www.page-meeting.org/?abstract=2547]
Poster: Oncology