Pharmacogenomic-pharmacokinetic study of selective estrogen-receptor modulators with intra-patient dose escalation in breast cancer
Pharmacogenomic-pharmacokinetic study of selective estrogen-receptor modulators with intra-patient dose escalation in breast cancer
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DOI：
10.1007/s12282-019-00952-9
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发表时间：
2019-09-01
期刊：
影响因子：
4
通讯作者：
Toi, Masakazu
中科院分区：
文献类型：
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作者：
Ishiguro, Hiroshi;Ohno, Shinji;Toi, Masakazu
CYP 2D 6多态性与他莫昔芬（TAM）疗效之间的关联尚未得到证实，部分原因是仅通过CYP 2D 6活性预测活性代谢物暴露不可靠。TAM剂量递增的疗效在TAM代谢不良者中似乎有限。由于托瑞米芬（TOR）侧链上的氯原子阻止了CYP 2D 6的4-羟基化，因此其对TOR活性转化的贡献很小。我们研究了TOR及其剂量递增在TAM代谢不良者中的作用。方法研究TAM和TOR的药代动力学（PK）和药物基因组学（PGx）。通过回归分析检查PK与CYP 2D 6抑制剂使用、吸烟状态和PGx之间的相关性。对于显示低内昔芬水平的患者，进行TOR的患者内剂量递增，并且TOR从40 mg增加至120 mg，持续>= 24周，并进行PK采样。总活性计算为通过其各自体外活性调整的每种活性代谢物的浓度总和。结果273例参与研究的患者中，内昔芬水平分别为50例和11例，< 15和< 7.5 ng/mL。CYP 2D 6基因型是TAM活性的主要决定因素（p < 0.01）。吸烟状态（p = 0.07）和CYP 2C 19表型（p = 0.07），但不是CYP 2D 6基因型（p = 0.61），对TOR活性显示出轻微的显着影响。TOR活性随着剂量的增加而显著增加，即使在TAM代谢不良者中也是如此，并且维持>= 24周。结论对于预计为TAM代谢不良的患者，TOR可能是TAM的有效替代方案。
Background An association between CYP2D6 polymorphisms and tamoxifen (TAM) efficacy has not been confirmed, partly due to unreliable prediction of active metabolite exposure solely by CYP2D6 activity. The efficacy of TAM dose escalation appears limited in poor TAM metabolizers. Since the chlorine atom on the side chain of toremifene (TOR) prevents 4-hydroxylation by CYP2D6, its contribution to active conversion of TOR is minor. We examined the role of TOR and its dose escalation among poor TAM metabolizers. Methods The pharmacokinetics (PK) and pharmacogenomics (PGx) of TAM and TOR were studied. Correlation between PK and CYP2D6 inhibitor use, smoking status, and PGx were examined by regression analysis. For patients showing low endoxifen levels, an intra-patient dose escalation of TOR was conducted, and TOR was increased from 40 to 120 mg for >= 24 weeks with PK sampling. Total activity was calculated as the sum of the concentration of each active metabolite adjusted by their respective in vitro activities. Results Fifty and 11 of the 273 participating patients had endoxifen levels < 15 and < 7.5 ng/mL, respectively. The CYP2D6 genotype was the major determinant for TAM activity (p < 0.01). Smoking status (p = 0.07) and the CYP2C19 phenotype (p = 0.07), but not the CYP2D6 genotype (p = 0.61), showed marginally significant effects on TOR activity. TOR activity increased significantly with dose escalation, even among poor TAM metabolizers, and was maintained for >= 24 weeks. Conclusion TOR might be a valid alternative to TAM in patients predicted to be poor TAM metabolizers.