Purpose: To overcome cytochrome P450 2D6 (CYP2D6) mediated tamoxifen resistance in postmenopausal early\nbreast cancer, CYP2D6 phenotype-adjusted tamoxifen dosing in patients with impaired CYP2D6 metabolism and/or\nthe application of endoxifen, the most potent tamoxifen metabolite, are alternative treatment options. To elucidate\nboth strategies comprehensively we used a physiologically-based pharmacokinetic (PBPK) modeling approach.\nMethods: Firstly simulation of increasing tamoxifen dosages was performed by a virtual clinical trial including\npopulations of CYP2D6 poor (PM), intermediate (IM) and extensive metabolizers (EM) (N = 8,000). Secondly we\nperformed PBPK-simulations under consideration of tamoxifen use plus concomitant increasing dosages of\nendoxifen (N = 7,000).\nResults: Our virtual study demonstrates that dose escalation of tamoxifen in IMs resulted in endoxifen steady-state\nplasma concentrations similar to CYP2D6 EMs whereas PMs did not reach EM endoxifen levels. Steady-state plasma\nconcentrations of tamoxifen, N-desmethyl-tamoxifen, 4-hydroxy-tamoxifen and endoxifen were similar in CYP2D6\nIMs and PMs versus EMs using once daily dosing of 20 mg tamoxifen and concomitant CYP2D6 phenotype-adjusted\nendoxifen dosing in IMs and PMs (1 mg/d and 3 mg/d, respectively).\nConclusion: In conclusion, we suggest that co-administration of endoxifen in tamoxifen treated early breast cancer\nwomen with impaired CYP2D6 metabolism is a promising alternative to reach plasma concentrations comparable\nto CYP2D6 EM patients.
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