SLCO1B1c.521T＞C基因多态性与大剂量甲氨蝶呤治疗儿童急性淋巴细胞白血病药代动力学及疗效评价
SLCO1B1c.521T＞C기인다태성여대제량갑안접령치료인동급성림파세포백혈병약대동역학급료효평개
SLCO1B1c.521T ＞ C gene polymorphisms are associated with high-dose methotrexate pharmacokinetics and clinical outcome of pediatric acute lymphoblastic leukemia
  • 万方数据
    中华儿科杂志 중화인과잡지
    Chinese Journal of Pediatrics
    2014年 10期 770-776 ,共7页

    张华年%何学连%李建新%汪洋%王诚%陈渝军%牛长河%高萍

    장화년%하학련%리건신%왕양%왕성%진투군%우장하%고평

    甲氨蝶呤%突变%药代动力学 甲氨蝶呤%突變%藥代動力學
    갑안접령%돌변%약대동역학
    Methotrexate%Mutation%Pharmacokinetics
    目的 探讨SLCO1B1c.521 T＞C基因变异对大剂量甲氨蝶呤治疗儿童急性淋巴细胞白血病(ALL)药代动力学和临床疗效的影响.方法 选择2008年1月至2013年12月武汉市儿童医院血液内科收治的82例ALL患儿为研究对象,依据基因分型结果,将患儿分为SLCO1B1c.521T＞C基因变异组和未变异组.参考ALL-BFM 2000化疗方案,甲氨蝶呤化疗剂量为3～5 g/m2静脉滴注给药;四氢叶酸于甲氨蝶呤用药36 h后开始解救,并根据第48小时甲氨蝶呤血药浓度进行调整.固相萃取高效液相色谱法(Spe-HPLC)分析24、48、72 h血清中甲氨蝶呤及其代谢产物7-OH甲氨蝶呤浓度.NLME群体药代动力学方法估算药代动力学参数;比较两组患儿药代动力学、毒性反应、四氢叶酸解救剂量,随访5年ALL复发率及无事件生存率.结果 82例ALL患儿中SLCO1B1c.521T＞C变异组21例[突变杂合子型(TC) 20例,突变纯合子型(CC)1例],未变异组[野生纯合子型(TT)]61例.SLCO1B1c.521T＞C变异组患儿48、72 h甲氨蝶呤血药浓度明显高于未变异组,差异有统计学意义[48 h:(1.00±1.41)比(0.34±0.17) μmol/L,t=2.131,P=0.046;72 h:(0.31 ±0.26)比(0.08±0.04)μmol/L;t=3.995,P=0.001].变异组48 h后甲氨蝶呤血药浓度曲线下面积(AUC48-∞)为(23.18±19.91)h·μmol/L,明显高于未变异组(t=4.025,P=0.001).变异组患儿超甲氨蝶呤血药浓度安全阈值(0.1 μmol/L)时间(TC＞01μmol/L)显著高于未变异组,差异有统计学意义[(95.3±22.0)比(67.1±7.5)h,t=5.880,P＜0.001];变异组患儿所需四氢叶酸解救平均剂量高于未变异组,差异有统计学意义[(312.7 ±287.8)比(140.6±27.5) mg/m2;=2.614,P=0.017].变异组患儿胃肠道和肝脏严重毒性反应(Ⅲ～Ⅳ级)的发生率均显著高于未变异组[胃肠道33％(7/21)比5％ (3/61);肝脏:24％(5/21)比2％(1/61)],差异均有统计学意义(x 2=9.275、8.289,P均＜0.05).变异组患儿住院天数(4.95±1.43)d,未变异组(4.05±0.22)d,差异有统计学意义(t =2.881,P=0.009).变异组5年累积复发率9％ (2/21),未变异组13％ (8/61).5年内变异组和未变异组无事件生存率分别为86％和87％,两组差异无统计学意义(x2=o.001,P=0.971).结论 SLCO1B1c.521T＞C基因变异是影响ALL患儿甲氨蝶呤药代动力学的重要因素,适当增加变异组患儿四氢叶酸解救强度,对降低甲氨蝶呤的严重毒性作用有益,但不影响大剂量甲氨蝶呤治疗长期疗效.
    목적 탐토SLCO1B1c.521 T＞C기인변이대대제량갑안접령치료인동급성림파세포백혈병(ALL)약대동역학화림상료효적영향.방법 선택2008년1월지2013년12월무한시인동의원혈액내과수치적82례ALL환인위연구대상,의거기인분형결과,장환인분위SLCO1B1c.521T＞C기인변이조화미변이조.삼고ALL-BFM 2000화료방안,갑안접령화료제량위3～5 g/m2정맥적주급약;사경협산우갑안접령용약36 h후개시해구,병근거제48소시갑안접령혈약농도진행조정.고상췌취고효액상색보법(Spe-HPLC)분석24、48、72 h혈청중갑안접령급기대사산물7-OH갑안접령농도.NLME군체약대동역학방법고산약대동역학삼수;비교량조환인약대동역학、독성반응、사경협산해구제량,수방5년ALL복발솔급무사건생존솔.결과 82례ALL환인중SLCO1B1c.521T＞C변이조21례[돌변잡합자형(TC) 20례,돌변순합자형(CC)1례],미변이조[야생순합자형(TT)]61례.SLCO1B1c.521T＞C변이조환인48、72 h갑안접령혈약농도명현고우미변이조,차이유통계학의의[48 h:(1.00±1.41)비(0.34±0.17) μmol/L,t=2.131,P=0.046;72 h:(0.31 ±0.26)비(0.08±0.04)μmol/L;t=3.995,P=0.001].변이조48 h후갑안접령혈약농도곡선하면적(AUC48-∞)위(23.18±19.91)h·μmol/L,명현고우미변이조(t=4.025,P=0.001).변이조환인초갑안접령혈약농도안전역치(0.1 μmol/L)시간(TC＞01μmol/L)현저고우미변이조,차이유통계학의의[(95.3±22.0)비(67.1±7.5)h,t=5.880,P＜0.001];변이조환인소수사경협산해구평균제량고우미변이조,차이유통계학의의[(312.7 ±287.8)비(140.6±27.5) mg/m2;=2.614,P=0.017].변이조환인위장도화간장엄중독성반응(Ⅲ～Ⅳ급)적발생솔균현저고우미변이조[위장도33％(7/21)비5％ (3/61);간장:24％(5/21)비2％(1/61)],차이균유통계학의의(x 2=9.275、8.289,P균＜0.05).변이조환인주원천수(4.95±1.43)d,미변이조(4.05±0.22)d,차이유통계학의의(t =2.881,P=0.009).변이조5년루적복발솔9％ (2/21),미변이조13％ (8/61).5년내변이조화미변이조무사건생존솔분별위86％화87％,량조차이무통계학의의(x2=o.001,P=0.971).결론 SLCO1B1c.521T＞C기인변이시영향ALL환인갑안접령약대동역학적중요인소,괄당증가변이조환인사경협산해구강도,대강저갑안접령적엄중독성작용유익,단불영향대제량갑안접령치료장기료효.
    Objective To provide guidance for the high-dose methotrexate (HD-MTX) treatment of pediatric acute lymphoblastic leukemia (ALL),and to understand the impact of SLCO1B1c.521T ＞ C (rs4149056) variant on methotrexate (MTX) pharmacokinetics and clinical outcome in children with ALL.Method Eighty-two children with ALL in Division of Hematology of Wuhan Children's Hospital from January 2008 to February 2013 were enrolled.All patients were genotyped for rs4149056 single nucleotide polymorphism (SNP) into wild-type group (TT genotype) and variant group (TC/CC genotype).According to the ALL-BFM 2000 protocol,all patients received intravenous infusion of MTX everv ten days at 3 to 5 g/m2.Leucovorin rescue was performed after 36 hours of the MTX administration and its dose was adjusted according to the MTX plasma concentration at 48 hours.The concentrations of MTX and its metabolite at 24,48 and 72 h were determined by high performance liquid chromatography with solid phase extraction.Population pharmacokinetic parameters were estimated by the NLME software.The pharmacokinetics,toxicity and leucovorin rescue was compared.The relapse rate within 5 years and event-free survival were followed up.Result Eighty-two pediatric patients were classified into two groups:variant group including 20 TC genotype carriers and one CC genotype carrier,wild-type group included 61 patients with TT genotype.Compared with wild-type group,plasma concentration of MTX at 48 and 72 h increased significantly [48 h:(1.00±1.41) vs.(0.34±0.17) μmol/L,t =2.131,P=0.046;72 h:(0.31 ± 0.26) vs.(0.08 ± 0.04) μmol/L; t =3.995,P =0.001].Area under the concentration time curve (AUC48-∞) of MTX significantly increased in variant group [(23.18± 19.91) vs.(5.66± 2.01) h · μmoL/L] (t =4.025,P =0.001).Time above the MTX safety threshold (TC＞0.1 μmol/L) increased significantly in variant group [(95.3 ±22.0) vs.(67.1 ±7.5) h,t =5.880,P ＜0.001].Rescue dosage of leucovorin in variant group was higher than that in wild-type group [(312.7 ±287.8) vs.(140.6 ±27.5)mg/m2,t =2.614,P =0.017].The children carrying rs4149056 C allele suffered from a higher frequency of serious adverse effect [gastrointestinal toxicity:33％ (7/21) vs.5％ (3/61) ; hepatic toxicity:24％ (5/21) vs.2％ (1/61)].The difference was statistically significant (x2 =9.275,8.289,all P ＜ 0.05).Hospital stay of variant group was significantly longer than that of wild-type [(4.95 ± 1.43) vs.(4.05 ±0.22) d,t =2.881,P =0.009].The relapse rate within 5 years of variant group and will-type group were 9％ (2/21) and 13％ (8/61),respectively.There were no significant differences in the event-free survival between the two groups (x2 =0.001,P =0.971).Conclusion The SLCO1B1 c.521T ＞ C variant was an important determinant of MTX pharmacokinetics.An appropriate leucovorin dose raise in variant group was beneficial to reducing the serious toxicity and did not affect the long-term clinical outcome.
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