Population pharmacokinetics of tamoxifen in patients with breast cancer

doi:10.12092/j.issn.1009-2501.2019.04.009

Abstract

Abstract:

AIM:To investigate the population pharmacokinetic characteristics of tamoxifen (TAM) in breast cancer patients and factors that might impact its clearance. METHODS: Blood samples of breast cancer patients who regularly took TAM were collected and the blood concentration of TAM and its metabolite Endoxifen was determined by HPLC-MS/MS and analyzed with nonlinear mixed-effect model (NONMEM). The population pharmacokinetics parameters were compared with those of volunteers in literatures. After that, 1 000 bootstraps were performed to validate the final model. RESULTS:A total of 29 patients took TAM. The mean age and BMI was (46.9±6.4) years and (23.70±2.87) kg/cm2, respectively. Typical population estimates of Ka, CLTAM, CLMET, VTAM, VEND, CLEND, Q were 0.830 h-1, 6.61 L/h, 0.707 L/h, 753 L, 400 L, 5.10 L/h, 61.8 L, respectively. Covariable screening showed OATP1B1*521 gene polymorphism and menopause time had an effect on metabolic constant CLTAM in the process of forward inclusion (P<0.05), but no significant covariable (P<0.001) was found in the process of backward elimination. The model validation of bootstraps results showed the success rate was 96.8%.CONCLUSION: The population pharmacokinetics model of TAM and END is established successfully. And it can provide some information for TAM clinical individualized medication from the perspective of pharmacometrics.

Key words: tamoxifen, breast cancer, population pharmacokinetics, OATP1B1

CLC Number:

WU Min, GUO Yiyun, XIE Haitang. Population pharmacokinetics of tamoxifen in patients with breast cancer[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2019, 24(4): 418-423.

References

［1］Cuzick J, Baum M. Tamoxifen and contralateral breast cancer［J］. Lancet, 1985, 2(8449): 282.
［2］Jordan VC.Tamoxifen: a most unlikely pioneering medicine［J］.Nat Rev Drug Discov,2003,2(3):205-213.
［3］Fisher B, Costantino JP, Wickerham DL, et al. Tamoxifen for the prevention of breast cancer: current status of the National Surgical Adjuvant Breast and Bowel Project P-1 study ［J］. J Natl Cancer Inst, 2005, 97(22): 1652-1662.
［4］International Breast Cancer Study Group, Colleoni M, Gelber S, et al. Tamoxifen after adjuvant chemotherapy for premenopausal women with lymph node-positive breast cancer: International Breast Cancer Study Group Trial 13-93［J］. J Clin Oncol, 2006, 24(9): 1332-1341.
［5］Early Breast Cancer Trialists' Collaborative Group, Davies C, Godwin J, et al. Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomised trials ［J］. Lancet, 2011, 378(9793): 771-784.
［6］Early Breast Cancer Trialists' Collaborative G. Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials ［J］. Lancet, 2005, 365(9472): 1687-1717.
［7］Early Breast Cancer Trialists' Collaborative Group. Effects of adjuvant tamoxifen and of cytotoxic therapy on mortality in early breast cancer. An overview of 61 randomized trials among 28,896 women［J］. N Engl J Med, 1988, 319(26): 1681-1692.
［8］Early Breast Cancer Trialists' Collaborative Group. Tamoxifen for early breast cancer ［J］. Cochrane Database Syst Rev, 2001(1): CD000486.
［9］芮建中, 张震, 李金恒. 群体药代动力学/群体药效动力学原理及研究方法［J］. 医学研究生学报, 2005, 18(3): 246-249.
［10］Sheiner LB. Learning versus confirming in clinical drug development ［J］. Clin Pharmacol Ther, 1997, 61(3): 275-291.
［11］张弨, 赵荣生, 翟所迪, 等. 群体药代动力学概述［J］. 中国临床药理学杂志, 2013, 29(8): 563-565.
［12］ter Heine R, Binkhorst L, de Graan AJ, et al. Population pharmacokinetic modelling to assess the impact of CYP2D6 and CYP3A metabolic phenotypes on the pharmacokinetics of tamoxifen and endoxifen［J］. Br J Clin Pharmacol, 2014, 78(3): 572-586.
［13］Ahmad A, Shahabuddin S, Sheikh S, et al. Endoxifen, a new cornerstone of breast cancer therapy: demonstration of safety, tolerability, and systemic bioavailability in healthy human subjects［J］. Clin Pharmacol Ther, 2010, 88(6): 814-817.
［14］陈冰, 杨婉花, 张伟霞, 等. 中国成年患者万古霉素群体药动学研究［J］. 药学与临床研究, 2013, 21(6): 605-609.
［15］Boeckmann A, Sheiner L, Beal S. NONMEM Users Guide ［M］. Part V: 102-103.
［16］凌静, 钱李轩, 丁俊杰, 等. 谷浓度采样设计和算法对群体和个体药动学参数估算的影响［J］. 药学学报, 2014, 49(5): 686-694.
［17］王亚萍, 牛小麟. 基因多态性的研究方法及其临床应用［J］. 临床医学, 2003, 23(9): 49-50.
［18］Pu Z, Zhang X, Chen Q, et al. Establishment of an expression platform of OATP1B1 388GG and 521CC genetic polymorphism and the therapeutic effect of tamoxifen in MCF-7 cells［J］. Oncol Rep, 2015, 33(5): 2420-2428.
［19］Zhang X, Pu Z, Ge J, et al. Association of CYP2D6*10, OATP1B1 A388G, and OATP1B1 T521C polymorphisms and overall survival of breast cancer patients after tamoxifen therapy ［J］. Med Sci Monit, 2015, 21: 563-569.
［20］Gao CM, Pu Z, He C, et al. Effect of OATP1B1 genetic polymorphism on the uptake of tamoxifen and its metabolite, endoxifen ［J］. Oncol Rep, 2017, 38(2): 1124-1132.

[1]	HE Lihua, ZHU Xiuzhi, JIANG Yizhou. Research progress on immunotherapy for triple-negative breast cancer [J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2023, 28(8): 842-853.
[2]	ZHANG Huyunlong, ZHU Xiuzhi, JIN Xi, SHAO Zhimin. Mechanisms of endocrine-resistance and therapeutic breakthroughs in hormone receptor-positive, HER2-negative breast cancer [J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2023, 28(8): 854-865.
[3]	FU Xiaoyu, KONG Deguang, LI Juanjuan. Treatment progress of triple positive breast cancer [J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2023, 28(8): 866-875.
[4]	LUO Shiping, ZHANG Jie, YU Yushuai, SONG Chuangui. Advances in targeted therapy for HER2-positive breast cancer [J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2023, 28(8): 876-886.
[5]	XIANG Yimei, ZHANG Ningning, HUANG Yuxin, ZENG Xiaohua. Research progress of biomarkers related to the efficacy of HER2 positive breast cancer [J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2023, 28(8): 887-897.
[6]	CHEN Keyu, HUANG Yuan, WANG Xiaojia, ZHENG Yabing. Clinical application and research progress of antibody drugs conjugation in breast cancer [J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2023, 28(8): 898-909.
[7]	LI Mengxi, ZHANG Kejing, XIA Fan. Research progress in vaccine for breast cancer [J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2023, 28(8): 918-925.
[8]	HUANG Zhiwei, LI Yi, XU Xiaoyong, ZHANG Lei, SHEN Yifeng, LI Huafang. Comparison of calculation results of five population pharmacokinetic analysis tools [J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2023, 28(5): 525-535.
[9]	LI Mengxue, HE Jie, YU Xiaxia, HU Linlin, SHAO Hua. Research progress in population pharmacokinetics of rituximab [J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2023, 28(4): 468-474.
[10]	WANG Zhi, ZHOU Xin, HE Xueru, FU Yuhao, XUN Xuejiao, LI Ying, DONG Zhanjun. Clinical research progress of palbociclib in treatment of breast cancer [J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2023, 28(2): 205-213.
[11]	LIU Lu, SHI Yufei, HE Qingfeng, XU Fengyan, WANG Kun, CAI Weimin, XIANG Xiaoqiang. Application of population modeling analysis to evaluate the impact of gene polymorphism on drug PK/PD [J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2023, 28(11): 1275-1282.
[12]	WANG Xiu, JI Qilin, PEI Wenjun, ZENG Ying. 3-bromopyruvate cholesterol ester enhances the sensitivity of breast cancer cells to tamoxifen [J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2023, 28(10): 1093-1100.
[13]	WU Shuai, YANG Jun, ZHENG Yun. Dual role of miRNA in breast cancer [J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2022, 27(7): 814-821.
[14]	SHI Jingbin, XIONG Yang. Research progress on interaction between tumor microenvironment and breast cancer cells leading to tumor metastasis [J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2022, 27(5): 562-574.
[15]	DONG Wei, HUANG Xiaoying, XIE Bingbin, TANG Xilan, LI Hongming, QIU Yumei, ZHAO Guowei, LIANG Xinli. Effects of oxypeucedanin on the resistance of breast cancer MCF-7/DOX cells to doxorubicin [J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2022, 27(3): 260-266.