伊马替尼血药浓度影响因素研究进展
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摘要
伊马替尼是一种小分子酪氨酸激酶抑制剂(TKIs),主要用于治疗费城染色体阳性的慢性粒细胞白血病(CML)和不可切除或发生转移的胃肠道间质瘤(GIST)。伊马替尼自上市以来显示出了较好的疗效,但研究发现,服用相同剂量药物时,达稳态时伊马替尼血浆谷浓度的差异大,而血浆谷浓度与药物反应及患者的临床获益密切相关。因此,研究伊马替尼血药浓度影响因素,对判断药物疗效、评价治疗效果、调整治疗方案和规避毒副反应等方面有重要意义。笔者将从病理生理状态、代谢酶和转运体的基因多态性、联合用药等方面探讨影响伊马替尼血药浓度的因素,旨在为临床合理用药、制定个体化给药方案提供参考。
Imatinib is a kind of tyrosine kinase inhibitors which is mainly used for the treatment of Philadelphia chromosome-positive chronic myelogenous leukemia(CML) and unresectable or metastatic gastrointestinal stromal tumors. Imatinib has shown good efficacy since its introduction to the market, but it has been found that steady-state trough plasma concentrations of imatinib vary widely at the same dose, and trough plasma concentrations were closely related with drug response and clinical benefit for patients. Therefore, it is of great significance to study the influencing factors of imatinib plasma concentration while judging drug efficacy, evaluating treatment effect, adjusting treatment regimen and avoiding toxicity. The authors explored the factors affecting the plasma concentration of imatinib concerning pathophysiological status, gene polymorphism of metabolic enzymes and transporters, and combination therapy, aiming to provide a reference for clinical rational drug use and individualized dosing regimen.
Imatinib is a kind of tyrosine kinase inhibitors which is mainly used for the treatment of Philadelphia chromosome-positive chronic myelogenous leukemia(CML) and unresectable or metastatic gastrointestinal stromal tumors. Imatinib has shown good efficacy since its introduction to the market, but it has been found that steady-state trough plasma concentrations of imatinib vary widely at the same dose, and trough plasma concentrations were closely related with drug response and clinical benefit for patients. Therefore, it is of great significance to study the influencing factors of imatinib plasma concentration while judging drug efficacy, evaluating treatment effect, adjusting treatment regimen and avoiding toxicity. The authors explored the factors affecting the plasma concentration of imatinib concerning pathophysiological status, gene polymorphism of metabolic enzymes and transporters, and combination therapy, aiming to provide a reference for clinical rational drug use and individualized dosing regimen.
引文
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[3] YinY, XiangJ, ShenChY, et al. Monitoring of plasma concentration of imatinib in patients with gastrointestinal stromal tumors and its significance [J]. Chin J Bases Clin Gen Surg (中国普外基础与临床杂志), 2017,24(02):158-162.
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[15] Barratt DT, Cox HK, Menelaou A, et al. CYP2C8 genotype significantly alters imatinib metabolism in chronic myeloid leukaemia patients [J]. Clin Pharmacokinet, 2017,56(8):977-985.
[16] Verboom MC, Visser L, Kouwen S, et al. Influence of CYP2C8 polymorphisms on imatinib steady-state trough level in chronic myeloid leukemia and gastrointestinal stromal tumor patients [J]. Pharmacogenet Genomics, 2017,27(6):223-226.
[17] Picard S, Titier K, Etienne G, et al. Trough imatinib plasma levels are associated with both cytogenetic and molecular responses to standard-dose imatinib in chronic myeloid leukemia [J]. Blood, 2007,109(8):3496-3499.
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[20] Dohse M, Scharenberg CS, Robey RW, et al. Comparison of ATP-binding cassette transporter interactions with the tyrosine kinase inhibitors imatinib, nilotinib, and dasatinib [J]. Drug Metab Dispos, 2010,38(8):1371-1380.
[21] Yamakawa Y, Hamada A, Nakashima R, et al. Association of genetic polymorphisms in the influx transporter SLCOLB3 and the efflux transporter ABCB1 with imatinib pharmacokinetics in patients with chronic myeloid leukemia [J]. Ther Drug Monit, 2011,33(2):244-50.
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[23] Francis J, Dubashi B, Sundaram R, et al. A study to explore the correlation of ABCB1, ABCG2, OCT1 genetic polymorphisms and trough level concentration with imatinib mesylate-induced thrombocytopenia in chronic myeloid leukemia patients [J]. Cancer Chemother Pharmacol, 2015,76(6):1185-1189.
[24] Di PA, Polillo M, Capecchi M, et al. The c.480C>G polymorphism of hOCT1 influences imatinib clearance in patients affected by chronic myeloid leukemia [J]. Pharmacogenomics J, 2014,14(4):328-335.
[25] Saito H. Pharmacokinetic impact of SLCOLA2 polymorphisms on imatinib disposition in patients with chronic myeloid leukemia [J]. Clin Pharmacol Ther, 2011,90(1):157-163.
[26] Druker BJ, Guilhot F, O'Brien SG, et al. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia [J]. N Engl J Med, 2006,355(23):2408-17.
[27] Bouchet S, Poulette S, Titier K, et al. Relationship between imatinib trough concentration and outcomes in the treatment of advanced gastrointestinal stromal tumours in a real-life setting [J]. Eur J Cancer, 2016,57:31-38.
[28] Hochhaus A, Larson RA, Guilhot F, et al. Long-term outcomes of imatinib treatment for chronic myeloid leukemia [J]. N Engl J Med, 2017,376(10):917-927.
[29] Bins S, Eechoute K, Kloth JSL, et al. Prospective analysis in gist patients on the role of alpha-1 acid glycoprotein in imatinib exposure [J]. Clin Pharmacokinet, 2016,56(3):1-6.
[30] Adeagbo BA, Olugbade TA, Durosinmi MA, et al. Population pharmacokinetics of imatinib in nigerians with chronic myeloid leukemia: Clinical implications for dosing and resistance [J]. J Clin Pharmacol, 2017,57(12):1554-1563.
[31] Golabchifar AA, Rezaee S, Ghavamzadeh A, et al. Population pharmacokinetics of imatinib in iranian patients with chronic-phase chronic myeloid leukemia[J]. Cancer Chemother Pharmacol,2014,74(1):85-93.
[2] Herviou P, Thivat E, Richard D, et al. Therapeutic drug monitoring and tyrosine kinase inhibitors [J]. Oncol Lett, 2016,12(2):1223-1232.
[3] YinY, XiangJ, ShenChY, et al. Monitoring of plasma concentration of imatinib in patients with gastrointestinal stromal tumors and its significance [J]. Chin J Bases Clin Gen Surg (中国普外基础与临床杂志), 2017,24(02):158-162.
[4] LiuXL, YaoHaiying, LiuYJ, et al. Relationship between blood drug level and efficacy of imatinib for chronic myeloid leukemia [J]. Chin J Mod Med(中国现代医学杂志), 2012,22(10):42-44.
[5] Teng JF, Mabasa VH, Ensom MH. The role of therapeutic drug monitoring of imatinib in patients with chronic myeloid leukemia and metastatic or unresectable gastrointestinal stromal tumors [J]. Ther Drug Monit, 2012,34(1):85-97.
[6] Peng B, Lloyd P, Schran H. Clinical pharmacokinetics of imatinib [J]. Clin Pharmacokinet, 2005,44(9):879-894.
[7] Pappas P, Karavasilis V, Briasoulis E, et al. Pharmacokinetics of imatinib mesylate in end stage renal disease[J]. A case study [J]. Cancer Chemother Pharmacol, 2005,56(4):358-360.
[8] Yoo C, Ryu MH, Kang BW, et al. Cross-sectional study of imatinib plasma trough levels in patients with advanced gastrointestinal stromal tumors: Impact of gastrointestinal resection on exposure to imatinib [J]. J Clin Oncol, 2010,28(9):1554-9.
[9] Muzio ED, Polticelli F, Trezza V, et al. Imatinib binding to human serum albumin modulates heme association and reactivity [J]. Arch Biochem Biophys, 2014,560(20):100-112.
[10] Haouala A, Widmer N, Guidi M, et al. Prediction of free imatinib concentrations based on total plasma concentrations in patients with gastrointestinal stromal tumours [J]. Br J Clin Pharmacol, 2013,75(4):1007-1018.
[11] Widmer N, Bardin C, Chatelut E, et al. Review of therapeutic drug monitoring of anticancer drugs part two--targeted therapies [J]. Eur J Cancer, 2014,50(12):2020-36.
[12] Zeng J, Xu P, Jiang ZP. Advances in gene polymorphisms related to pharmacokinetics of imatinib [J]. Chin J Clin Pharmacol (中国临床药理学杂志), 2017,33(2):185-188.
[13] Seong SJ, Lim M, Sohn SK, et al. Influence of enzyme and transporter polymorphisms on trough imatinib concentration and clinical response in chronic myeloid leukemia patients [J]. Ann Oncol, 2013,24(3):756-760.
[14] Harivenkatesh N, Kumar L, Bakhshi S, et al. Influence of MDR1 and CYP3A5 genetic polymorphisms on trough levels and therapeutic response of imatinib in newly diagnosed patients with chronic myeloid leukemia [J]. Pharmacol Res, 2017,120(14 Supplement):138-145.
[15] Barratt DT, Cox HK, Menelaou A, et al. CYP2C8 genotype significantly alters imatinib metabolism in chronic myeloid leukaemia patients [J]. Clin Pharmacokinet, 2017,56(8):977-985.
[16] Verboom MC, Visser L, Kouwen S, et al. Influence of CYP2C8 polymorphisms on imatinib steady-state trough level in chronic myeloid leukemia and gastrointestinal stromal tumor patients [J]. Pharmacogenet Genomics, 2017,27(6):223-226.
[17] Picard S, Titier K, Etienne G, et al. Trough imatinib plasma levels are associated with both cytogenetic and molecular responses to standard-dose imatinib in chronic myeloid leukemia [J]. Blood, 2007,109(8):3496-3499.
[18] Nebot N, Crettol S, D'Esposito F, et al. Participation of CYP2C8 and CYP3A4 in the n-demethylation of imatinib in human hepatic microsomes [J]. Br J Pharmacol, 2010,161(5):1059-1069.
[19] Filppula AM, Neuvonen M, Laitila J, et al. Autoinhibition of CYP3A4 leads to important role of CYP2C8 in imatinib metabolism: Variability in CYP2C8 activity may alter plasma concentrations and response [J]. Drug Metab Dispos, 2013,41(1):50-59.
[20] Dohse M, Scharenberg CS, Robey RW, et al. Comparison of ATP-binding cassette transporter interactions with the tyrosine kinase inhibitors imatinib, nilotinib, and dasatinib [J]. Drug Metab Dispos, 2010,38(8):1371-1380.
[21] Yamakawa Y, Hamada A, Nakashima R, et al. Association of genetic polymorphisms in the influx transporter SLCOLB3 and the efflux transporter ABCB1 with imatinib pharmacokinetics in patients with chronic myeloid leukemia [J]. Ther Drug Monit, 2011,33(2):244-50.
[22] Takahashi N, Miura M, Scott SA, et al. Influence of CYP3A5 and drug transporter polymorphisms on imatinib trough concentration and clinical response among patients with chronic phase chronic myeloid leukemia [J]. J Hum Genet, 2010,55(11):731-737.
[23] Francis J, Dubashi B, Sundaram R, et al. A study to explore the correlation of ABCB1, ABCG2, OCT1 genetic polymorphisms and trough level concentration with imatinib mesylate-induced thrombocytopenia in chronic myeloid leukemia patients [J]. Cancer Chemother Pharmacol, 2015,76(6):1185-1189.
[24] Di PA, Polillo M, Capecchi M, et al. The c.480C>G polymorphism of hOCT1 influences imatinib clearance in patients affected by chronic myeloid leukemia [J]. Pharmacogenomics J, 2014,14(4):328-335.
[25] Saito H. Pharmacokinetic impact of SLCOLA2 polymorphisms on imatinib disposition in patients with chronic myeloid leukemia [J]. Clin Pharmacol Ther, 2011,90(1):157-163.
[26] Druker BJ, Guilhot F, O'Brien SG, et al. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia [J]. N Engl J Med, 2006,355(23):2408-17.
[27] Bouchet S, Poulette S, Titier K, et al. Relationship between imatinib trough concentration and outcomes in the treatment of advanced gastrointestinal stromal tumours in a real-life setting [J]. Eur J Cancer, 2016,57:31-38.
[28] Hochhaus A, Larson RA, Guilhot F, et al. Long-term outcomes of imatinib treatment for chronic myeloid leukemia [J]. N Engl J Med, 2017,376(10):917-927.
[29] Bins S, Eechoute K, Kloth JSL, et al. Prospective analysis in gist patients on the role of alpha-1 acid glycoprotein in imatinib exposure [J]. Clin Pharmacokinet, 2016,56(3):1-6.
[30] Adeagbo BA, Olugbade TA, Durosinmi MA, et al. Population pharmacokinetics of imatinib in nigerians with chronic myeloid leukemia: Clinical implications for dosing and resistance [J]. J Clin Pharmacol, 2017,57(12):1554-1563.
[31] Golabchifar AA, Rezaee S, Ghavamzadeh A, et al. Population pharmacokinetics of imatinib in iranian patients with chronic-phase chronic myeloid leukemia[J]. Cancer Chemother Pharmacol,2014,74(1):85-93.