Abstract：Multiple target tyrosine kinase inhibitors are commonly used in clinical as anti-tumor drugs, which can promote tumor cell apoptosis by inhibiting cell signal transduction, with high selectivity and few side effects. At present, it is widely used in the treatment of non-small cell lung cancer, metastatic renal cancer, thyroid cancer and hematological malignancies. However, the clinical efficacy and pharmacokinetic characteristics of these drugs are affected by many factors, and there are great individual differences. In recent years, the study of population pharmacokinetics is emerging and is widely used in the study of many drugs. In this paper, the pharmacokinetic characteristics and influencing factors of axitinib, imatinib, erlotinib and sunitinib in cancer patients and healthy people were summarized through the retrieval of relevant literature, and then the progress of pharmacokinetic research of tyrosine kinase inhibitors(TKIs) was reviewed. The pharmacokinetic characteristics in different tumor types were analyzed and the related covariates were summarized. The results showed that demographic factors, gene polymorphism, blood biochemical indexes, combined use of drugs and liver and kidney function were important factors affecting metabolism in vivo. Factors such as experimental design and model construction may be the important reasons for the differences in research results. The purpose of this study is to provide a reference for making a reasonable and safe drug therapy plan.
刘婉秋, 高敬林, 冯章英, 陈珊珊, 梁玉, 王明霞. 多靶点酪氨酸激酶抑制剂治疗恶性肿瘤的群体药动学研究进展[J]. 中国药学杂志, 2020, 55(13): 1060-1067.
LIU Wan-qiu, GAO Jing-lin, FENG Zhang-ying, CHEN Shan-shan, LIANG Yu, WANG Ming-xia. Research Progress in Population Pharmacokinetics of Multiple Target Tyrosine Kinase Inhibitors in the Treatment of Malignant Tumors. Chinese Pharmaceutical Journal, 2020, 55(13): 1060-1067.
QIU H B, SUN X W, ZHOU Z W, et al. Updates on adjuvant therapy in gastrointestinal stromal tumor[J]. Chin J Gastrointest Surg(中华胃肠外科杂志), 2017, 20(9):961-965.
HERRMANN J. Tyrosine kinase inhibitors and vascular toxicity: impetus for a classification system?[J]. Curr Oncol Rep, 2016, 18(6):33.
SONG Y N, ZHANG H R, YIN D D, et al. Advances in research of small molecule tyrosine kinase inhibitors for targeted cancer therapy[J]. Chin Pharm J(中国药学杂志), 2016, 51(3):165-171.
RINI B I, GARRETT M, POLAND B, et al. Axitinib in metastatic renal cell carcinoma:results of a pharmacokinetic and pharmacodynamic analysis[J]. J Clin Pharmacol, 2013, 53(5):491-504.
TORTORICI M A, COHEN E E, PITHAVALA Y K, et al. Pharmacokinetics of single-agent axitinib across multiple solid tumor types[J]. Cancer Chemother Pharmacol, 2014, 74(6):1279-1289.
WHITE-KONING M, CIVADE E, GEOERGER B, et al. Population analysis of erlotinib in adults and children reveals pharmacokinetic characteristics as the main factor explaining tolerance particularities in children[J]. Clin Cancer Res, 2011, 17(14):4862-4871.
JIAO Z. Basic Population Pharmacokinetic and Pharmacodynamic Analysis(基础群体药动学和药效学分析) [M].Beijing:Science Press, 2019:23-57.
FUKUDO M, IKEMI Y, TOGASHI Y, et al. Population pharmacokinetics/pharmacodynamics of erlotinib and pharmacogenomic analysis of plasma and cerebrospinal fluid drug concentrations in Japanese patients with non-small cell lung cancer[J]. Clin Pharmacokinetics, 2013, 52(7):593-609.
SCHMIDLI H, PENG B, RIVIERE G J, et al. Population pharmacokinetics of imatinib mesylate in patients with chronic-phase chronic myeloid leukaemia:results of a phase Ⅲ study[J]. Br J Clin Pharm, 2005, 60(1):35-44.
MENON-ANDERSEN D, MONDICK J T, JAYARAMAN B, et al. Population pharmacokinetics of imatinib mesylate and its metabolite in children and young adults[J]. Cancer Chemother Pharmacol, 2009, 63(2):229-238.
DELBALDO C, CHATELUT E, RE M, et al. Pharmacokinetic-pharmacodynamic relationships of imatinib and its main metabolite in patients with advanced gastrointestinal stromal tumors[J]. Clin Cancer Res, 2006, 12(20 Pt 1):6073-6078.
XU P, WANG Q, JIANG Z P, et al. Population pharmacokinetic and pharmacogenetics of imatinib in Chinese patients with chronic myeloid leukemia[J]. Pharmacogenomics, 2019, 20(4):251-260.
KHOSRAVAN R, MOTZER R J, FUMAGALLI E, et al. Population pharmacokinetic/pharmacodynamic modeling of sunitinib by dosing schedule in patients with advanced renal cell carcinoma or gastrointestinal stromal tumor[J]. Clin Pharmacokinet, 2016, 55(10):1251-1269.
WIDMER N, DECOSTERD L A, CSAJKA C, et al. Population pharmacokinetics of imatinib and the role of alpha-acid glycoprotein[J]. Br J Clin Pharmacol, 2006, 62(1):97-112.
ADEAGBO B A, OLUGBADE T A, DUROSINMI M A, 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.
KIM D H, SRIHARSHA L, XU W, et al. Clinical relevance of a pharmacogenetic approach using multiple candidate genes to predict response and resistance to imatinib therapy in chronic myeloid leukemia[J]. Clin Cancer Res, 2009, 15(14):4750-4758.
TAKAHASHI N, MIURA M, SCOTT S A, 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 Human Genet, 2010, 55(11):731-737.
ENDO-TSUKUDE C, SASAKI J I, SAEKI S, et al. Population pharmacokinetics and adverse events of erlotinib in Japanese patients with non-small-cell lung cancer:impact of genetic polymorphisms in metabolizing enzymes and transporters[J]. Biol Pharm Bull, 2018, 41(1):47-56.
MAHON F X, BELLOC F, LAGARDE V, et al. MDR1 gene overexpression confers resistance to imatinib mesylate in leukemia cell line models[J]. Blood, 2003, 101(6):2368-2373.
GURNEY H, WONG M, BALLEINE R L, et al. Imatinib disposition and ABCB1 (MDR1, P-glycoprotein) genotype[J]. Clin Pharmacol Ther, 2007, 82(1):33-40.
DULUCQ S, KRAJINOVIC M J G M. The pharmacogenetics of imatinib[J]. Genome Med,2(11):85.
IGARASHI R, INOUE T, FUJIYAMA N, et al. Contribution of UGT1A1 genetic polymorphisms related to axitinib pharmacokinetics to safety and efficacy in patients with renal cell carcinoma[J]. Med Oncol, 2018, 35(4):51.
BOLTON A E, PENG B, HUBERT M, et al. Effect of rifampicin on the pharmacokinetics of imatinib mesylate (Gleevec, STI571) in healthy subjects[J]. Cancer Chemother Pharmacol, 2004, 53(2):102-106.
O′BRIEN S G, MEINHARDT P, BOND E, et al. Effects of imatinib mesylate (STI571, Glivec) on the pharmacokinetics of simvastatin, a cytochrome p450 3A4 substrate, in patients with chronic myeloid leukaemia[J]. Br J Cancer, 2003, 89(10):1855-1859.
DUCKETT D R, CAMERON M D. Metabolism considerations for kinase inhibitors in cancer treatment[J]. Exp Opinion Drug Metab Toxicol, 2010, 6(10):1175-1193.
MARCHETTI S, DE VRIES N A, BUCKLE T, et al. Effect of the ATP-binding cassette drug transporters ABCB1, ABCG2, and ABCC2 on erlotinib hydrochloride (Tarceva) disposition in in vitro and in vivo pharmacokinetic studies employing Bcrp1-/-/Mdr1a/1b-/-(triple-knockout) and wild-type mice[J]. Mol Cancer Ther, 2008, 7(8):2280-2287.
KODAIRA H, KUSUHARA H, USHIKI J, et al. Kinetic analysis of the cooperation of P-glycoprotein (P-gp/Abcb1) and breast cancer resistance protein (Bcrp/Abcg2) in limiting the brain and testis penetration of erlotinib, flavopiridol, and mitoxantrone[J]. J Pharmacol Exp Ther, 2010, 333(3):788-796.
DY G K, INFANTE J R, ECKHARDT S G, et al. Phase Ib trial of the oral angiogenesis inhibitor pazopanib administered concurrently with erlotinib[J]. Invest New Drugs, 2013, 31(4):891-899.
EMOTO-YAMAMOTO Y, IIDA S, KAWANISHI T, et al. Population pharmacokinetics of erlotinib in Japanese patients with advanced non-small cell lung cancer[J]. J Clin Pharm Ther, 2015, 40(2):232-239.
LU J F, EPPLER S M, WOLF J, et al. Clinical pharmacokinetics of erlotinib in patients with solid tumors and exposure-safety relationship in patients with non-small cell lung cancer[J]. Clin Pharmacol Ther, 2006, 80(2):136-145.
PETAIN A, KATTYGNARATH D, AZARD J, et al. Population pharmacokinetics and pharmacogenetics of imatinib in children and adults[J]. Clin Cancer Res, 2008, 14(21):7102-7109.
TORTORICI M A, TOH M, RAHAVENDRAN S V, et al. Influence of mild and moderate hepatic impairment on axitinib pharmacokinetics[J]. Invest New Drugs, 2011, 29(6):1370-1380.
CHEN Y, RINI B I, MOTZER R J, et al. Effect of renal impairment on the pharmacokinetics and safety of axitinib[J]. Target Oncol, 2016, 11(2):229-234.
USUI J, GLEZERMAN I G, SALVATORE S P, et al. Clinicopathological spectrum of kidney diseases in cancer patients treated with vascular endothelial growth factor inhibitors:a report of 5 cases and review of literature[J]. Human Pathol, 2014, 45(9):1918-1927.
CHEN Y, RINI B I, BAIR A H, et al. Population pharmacokinetic-pharmacodynamic modelling of 24-h diastolic ambulatory blood pressure changes mediated by axitinib in patients with metastatic renal cell carcinoma[J]. Clin Pharmacokinetics, 2015, 54(4):397-407.
WILKINSON G R. Cytochrome P4503A (CYP3A) metabolism: prediction of in vivo activity in humans[J]. J Pharmacokinetics Biopharm,1996, 24(5):475-490.