Dickschen Kristin, Eissing Thomas, Mürdter Thomas, Schwab Matthias, Willmann Stefan, Hempel Georg
Institut für Pharmazeutische und Medizinische Chemie, Klinische Pharmazie, Westfälische Wilhelms-Universität Münster, Corrensstrasse 48, Münster, 48149 Germany ; Computational Systems Biology, Bayer Technology Services GmbH, Building 9115, Leverkusen, 51368 Germany.
Computational Systems Biology, Bayer Technology Services GmbH, Building 9115, Leverkusen, 51368 Germany.
Springerplus. 2014 Jun 5;3:285. doi: 10.1186/2193-1801-3-285. eCollection 2014.
To overcome cytochrome P450 2D6 (CYP2D6) mediated tamoxifen resistance in postmenopausal early breast cancer, CYP2D6 phenotype-adjusted tamoxifen dosing in patients with impaired CYP2D6 metabolism and/or the application of endoxifen, the most potent tamoxifen metabolite, are alternative treatment options. To elucidate both strategies comprehensively we used a physiologically-based pharmacokinetic (PBPK) modeling approach.
Firstly simulation of increasing tamoxifen dosages was performed by a virtual clinical trial including populations of CYP2D6 poor (PM), intermediate (IM) and extensive metabolizers (EM) (N = 8,000). Secondly we performed PBPK-simulations under consideration of tamoxifen use plus concomitant increasing dosages of endoxifen (N = 7,000).
Our virtual study demonstrates that dose escalation of tamoxifen in IMs resulted in endoxifen steady-state plasma concentrations similar to CYP2D6 EMs whereas PMs did not reach EM endoxifen levels. Steady-state plasma concentrations of tamoxifen, N-desmethyl-tamoxifen, 4-hydroxy-tamoxifen and endoxifen were similar in CYP2D6 IMs and PMs versus EMs using once daily dosing of 20 mg tamoxifen and concomitant CYP2D6 phenotype-adjusted endoxifen dosing in IMs and PMs (1 mg/d and 3 mg/d, respectively).
In conclusion, we suggest that co-administration of endoxifen in tamoxifen treated early breast cancer women with impaired CYP2D6 metabolism is a promising alternative to reach plasma concentrations comparable to CYP2D6 EM patients.
为克服细胞色素P450 2D6（CYP2D6）介导的绝经后早期乳腺癌患者对他莫昔芬的耐药性，对CYP2D6代谢受损患者进行CYP2D6表型调整的他莫昔芬给药和/或应用他莫昔芬最有效的代谢产物4-羟基他莫昔芬是替代治疗方案。为全面阐明这两种策略，我们采用了基于生理的药代动力学（PBPK）建模方法。
首先，通过一项虚拟临床试验对增加他莫昔芬剂量进行模拟，该试验纳入了CYP2D6慢代谢者（PM）、中代谢者（IM）和快代谢者（EM）群体（N = 8000）。其次，我们在考虑使用他莫昔芬并同时增加4-羟基他莫昔芬剂量的情况下进行了PBPK模拟（N = 7000）。
我们的虚拟研究表明，IMs中他莫昔芬剂量递增导致4-羟基他莫昔芬稳态血浆浓度与CYP2D6 EMs相似，而PMs未达到EMs的4-羟基他莫昔芬水平。对于使用每日一次20 mg他莫昔芬给药且IMs和PMs同时进行CYP2D6表型调整的4-羟基他莫昔芬给药（分别为1 mg/d和3 mg/d）的情况，CYP2D6 IMs和PMs与EMs中的他莫昔芬、N-去甲基他莫昔芬、4-羟基他莫昔芬和4-羟基他莫昔芬的稳态血浆浓度相似。
总之，我们建议在接受他莫昔芬治疗的CYP2D6代谢受损的早期乳腺癌女性中联合使用4-羟基他莫昔芬，这是达到与CYP2D6 EM患者相当的血浆浓度的一种有前景的替代方法。
