Mueller-Schoell Anna, Michelet Robin, Klopp-Schulze Lena, van Dyk Madelé, Mürdter Thomas E, Schwab Matthias, Joerger Markus, Huisinga Wilhelm, Mikus Gerd, Kloft Charlotte
Department of Clinical Pharmacy and Biochemistry, Institute of Pharmacy, Freie Universitaet Berlin, 12169 Berlin, Germany.
Graduate Research Training Program PharMetrX, 12169 Berlin, Germany.
Cancers (Basel). 2021 May 18;13(10):2432. doi: 10.3390/cancers13102432.
Tamoxifen is used worldwide to treat estrogen receptor-positive breast cancer. It is extensively metabolized, and minimum steady-state concentrations of its metabolite endoxifen (C) >5.97 ng/mL have been associated with favorable outcome. Endoxifen formation is mediated by the enzyme CYP2D6, and impaired CYP2D6 function has been associated with lower C . In the Women's Healthy Eating and Living (WHEL) study proposing the target concentration, 20% of patients showed subtarget C at tamoxifen standard dosing. CYP2D6 allele frequencies vary largely between populations, and as 87% of the patients in the WHEL study were White, little is known about the risk for subtarget C in other populations. Applying pharmacokinetic simulations, this study investigated the risk for subtarget C at tamoxifen standard dosing and the need for dose individualization in nine different biogeographical groups with distinct CYP2D6 allele frequencies. The high variability in CYP2D6 allele frequencies amongst the biogeographical groups resulted in an up to three-fold difference in the percentages of patients with subtarget C. Based on their CYP2D6 allele frequencies, East Asian breast cancer patients were identified as the population for which personalized, model-informed precision dosing would be most beneficial (28% of patients with subtarget C).
他莫昔芬在全球范围内用于治疗雌激素受体阳性乳腺癌。它会被广泛代谢，其代谢产物4-羟基他莫昔芬（endoxifen，C）的最低稳态浓度>5.97 ng/mL与良好预后相关。4-羟基他莫昔芬的形成由细胞色素P450 2D6（CYP2D6）酶介导，CYP2D6功能受损与较低的C浓度相关。在提出目标浓度的女性健康饮食与生活（Women's Healthy Eating and Living，WHEL）研究中，20%的患者在他莫昔芬标准剂量下显示C浓度低于目标值。CYP2D6等位基因频率在不同人群中差异很大，由于WHEL研究中87% 的患者为白人，对于其他人群中C浓度低于目标值的风险知之甚少。本研究通过药代动力学模拟，调查了九个具有不同CYP2D6等位基因频率的不同生物地理群体在他莫昔芬标准剂量下C浓度低于目标值的风险以及剂量个体化的必要性。生物地理群体中CYP2D6等位基因频率的高度变异性导致C浓度低于目标值的患者百分比相差高达三倍。基于其CYP2D6等位基因频率，东亚乳腺癌患者被确定为个性化、模型指导的精准给药最有益的人群（28% 的患者C浓度低于目标值）。
