Mueller-Schoell, Anna, Klopp-Schulze, Lena, Schroth, Werner, Murdter, Thomas, Michelet, Robin, Brauch, Hiltrud, Huisinga, Wilhelm, Joerger, Markus, Neven, Patrick, Koolen, Stijn L.W., Mathijssen, Ron H.J., Copson, Ellen, Eccles, Diana, Chen, Sylvia, Chowbay, Balram, Tfayli, Arafat, Khoueiry-Zgheib, Nathalie, Schwab, Matthias and Kloft, Charlotte (2020) Obesity alters endoxifen plasma levels in young breast cancer patients: pharmacometric simulation approach. Clinical Pharmacology and Therapeutics, 108 (3), 661-670. (doi:10.1002/cpt.1960).
Abstract
Endoxifen is the most important metabolite of the prodrug tamoxifen. High interindividual variability in endoxifen steady-state concentrations (CSS,min ENDX) is observed under tamoxifen standard dosing breast cancer patients that do not reach endoxifen concentrations above a proposed therapeutic threshold of 5.97 ng/mL may be at higher recurrence risk. In this investigation, 10 clinical tamoxifen studies were pooled (nPatients=1388) to investigate influential factors on CSS,min ENDX using nonlinear mixed-effects modelling. Age and body weight were found to significantly impact CSS,min ENDX in addition to CYP2D6 phenotype. Compared to post-menopausal patients, pre-menopausal patients had a 30% higher risk for subtarget CSS,min ENDX at tamoxifen 20 mg per day. In treatment simulations for distinct patient subpopulations, young overweight patients had a 3.1-13.8-fold higher risk for subtarget CSS,min ENDX compared to elderly low-weight patients. Considering ever-rising obesity rates and the clinical importance of tamoxifen for pre-menopausal patients, this subpopulation may benefit most from individualised tamoxifen dosing.
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