大剂量甲氨蝶呤消除相血药浓度及其影响因素

目的分析大剂量甲氨蝶呤(MTX)化疗消除相血药浓度,并探讨其影响因素。方法本研究分析33例ALL患儿,230个疗程,24 h输注大剂量MTX(3 g.m-2)。检测MTX开始输注第1小时、第6小时、第23小时(稳态血药浓度)和第48小时的血药浓度(C48);如果C48>0.40μmol.L-1,再测第72小时的血药浓度(C72);以此类推,每24 h测血药浓度1次,直至MTX血药浓度<0.25μmol.L-1。结果大剂量MTX化疗后消除相血药浓度不同疗程间差异很大。大多数疗程MTX排泄很快,有201个疗程(占87%)C72<0.25μmol.L-1;然而也有少数疗程MTX排泄很慢,有14个疗程(占6%)C96>0.25μmol.L-1。不同疗程间C48为0.02~8.86μmol.L-1,中位数0.20μmol.L-1。有24个疗程(占10%)C48>1μmol.L-1,称为排泄延迟。不同患儿间C48有统计学差异(P=0.000)。导致C48增高的危险因素有男童、化疗前1周内有尿常规异常、化疗前2周内并感染和化疗同时静脉应用头孢曲松(P<0.05)。导致消除相MTX排泄延迟的危险因素有MTX稳态血药浓度高、M...     

淋巴系恶性肿瘤患儿大剂量氨甲蝶呤剂量个体化的临床研究

目的对淋巴系恶性肿瘤患儿进行HDMTX剂量个体化的临床研究。方法采用NONMEM软件,根据27例淋巴系恶性肿瘤患儿的99疗程HDMTX的MTX血浆浓度数据建立HDMTX的PPK模型。用此PPK模型结合MTX开始后第l h和第6h的血浆浓度,用贝叶斯法对10疗程HDMTX进行剂量个体化研究。结果HDMTX的稳态血浆浓度(Cpss)预测值在目标值范围内的7疗程中有6疗程的实测值在目标范围内;对预测值不在目标范围内的3疗程经贝叶斯法进行剂量调整后,Cpss实测值均在Cpss目标范围内。对MTX清除相对缓慢的4疗程,预测MTX血浆浓度≤0.25μmol/L的时间,预测时间和实测时间之差为0~2h。结论10疗程HDMTX的个体化研究显示,本研究建立的HDMTX的PPK模型预测较准确,个体化效果较好。     

大剂量甲氨喋呤治疗急性淋巴细胞白血病的血药浓度研究

目的　通过对甲氨喋呤 (MTX)治疗急性淋巴细胞白血病的血药浓度研究 ,探讨MTX剂量、血药浓度、效应、毒副作用等方面的关系 ,以及血药浓度检测的临床意义。方法　荧光偏振免疫分析法检测不同剂量MTX治疗的血药浓度 ,结合临床资料综合分析。结果　 1.第 2 4hMTX的血清浓度随剂量增加而增加 ;白血病复发率随浓度增加而下降 ,分别为 4 0 %、33.3%、2 5 % ;2 .鞘注前脑脊液 (CSF)浓度均低于有效浓度 ,因此须加鞘注治疗 ;3.本研究中MTX血药浓度均低于发生严重毒副作用的高危浓度 ,毒副作用均较轻微。结论　MTX血药浓度研究为实施合理的个体化治疗方案提供客观依据     

维族、汉族急性淋巴细胞白血病患儿甲氨蝶呤不良反应探讨

目的：通过对维吾尔族及汉族急性淋巴细胞白血病（ALL）患儿甲氨蝶呤（MTX）血药浓度监测结果的分析,为MTX不良反应的发生提供判断依据。方法：根据24 h MTX血药浓度监测结果,将28例（汉族 15 例,维吾尔族 13 例）接受大剂量MTX化疗的ALL患儿分为>10 μmol/L与≤10 μmol/L组;根据48 h MTX血药浓度监测结果分为>1.0 μmol/L与≤1.0 μmol/L组。采用酶放大免疫测定法对行MTX治疗的所有患儿给药后24 h及48 h血药浓度进行检测并观察不良反应发生情况。结果：不良反应发生率在不同24 h MTX血药浓度组间差异无统计学意义(P>0.05);48 h MTX血药浓度>1.0 μmol/L组的消化道反应及黏膜损害发生率高于血药浓度≤1.0 μmol/L组 (P0.05);汉族患儿24 h及48 h MTX血药浓度均高于维吾尔族(P<0.05);除消化道反应外,汉族患儿肝功能异常、黏膜损害及骨髓抑制的发生率高于维吾尔族患儿 (P<0.05)。结论：24 h MTX血药浓度不能预测不良反应的发生,48 h MTX血药浓度对不良反应的发生有一定预测价值;24 h、48 h MTX血药浓度及不良反应发生率在维吾尔族及汉族间存在差异;MTX血药浓度监测结果可能对及时调整MTX用量,从而达到MTX个体化治疗具有重要意义。     

儿童急性淋巴细胞白血病治疗中甲氨蝶呤血药浓度和脑脊液浓度的相关性

目的探讨儿童急性淋巴细胞白血病(ALL)大剂量甲氨蝶呤(HDMTX)治疗时甲氨蝶呤(MTX)血浆和脑脊液浓度的水平,以及同给药剂量、不良反应发生情况之间的关系。方法回顾性分析2015年1月-2017年1月在我院小儿血液科住院治疗的30名ALL患儿,共117例次HDMTX治疗。依据CCLG-ALL2008方案危险度分层,分成两组,A组:MTX为2g/m~2,B组:MTX为5g/m~2,进行多个时间点血药浓度和MTX开始后0. 5 h脑脊液药物浓度检测,对取得的药物浓度数据进行统计分析。结果 (1)B组患儿各时间点平均血药浓度和MTX开始后0.5 h脑脊液浓度均高于A组(P <0.05);(2)B组患儿骨髓抑制、肝功损害及口腔溃疡的发生率明显高于A组(P<0.05),其他不良反应的发生率差异无显著性(P>0. 05);两组患儿MTX开始后0.5h脑脊液药物浓度和血药浓度成正相关(P<0.01)。结论 (1)血浆和脑脊液MTX浓度同MTX给药剂量正相关。(2)MTX剂量越高,骨髓抑制、肝功损害、黏膜损害越严重,其他不良反应则无明显差异。(3)血药浓度决定MTX开始后0.5 h脑脊液浓度。     

丙戊酸钠治疗癫痫儿童个体化用药血药浓度监测及临床应用研究

目的：探讨丙戊酸钠(VPA)治疗癫痫儿童药物剂量与血药浓度之间的关系以及在血药浓度监测下调节个体化给药剂量的临床意义。为开展儿童群体药代动力学的研究奠定基础。方法：选择单用VPA治疗的癫痫患儿90例,在服药5～7个半衰期(t1/2=5～20 h)后,于晨空腹采静脉血2 ml,用荧光偏振免疫分析仪测定。结果：服药剂量为每日10～30 mg/kg时,血药浓度与剂量呈正相关(r=0.56,P30 kg组呈中度相关(r=0.56)。结论：在血药浓度监测下调整个体的给药剂量,可以取得较好的临床疗效。     

应用注射泵和输液泵持续输注大剂量甲氨蝶呤的效果比较

目的比较注射泵和输注泵在持续输注大剂量甲氨蝶呤(HDMTX)中的应用效果,为临床选择最佳输注方式提供依据。方法对2012年9月-2014年10月在我院儿科确诊的110例急性淋巴细胞白血病(ALL)患儿,在巩固治疗阶段共接受440例次HDMTX治疗时的临床资料进行回顾性分析。根据HDMTX输注方法将其分为注射泵组和输液泵组,2012年9月-2013年8月使用输液泵输注HDMTX的患儿为输液泵组,2013年9月-2014年10月使用注射泵输注HDMTX的患儿为注射泵组。在化疗前均留置经外周中心静脉导管(PICC)。统计和分析两组患儿的HDMTX持续输注的完成时间、MTX开始后24 h和48 h的血药浓度及其相关毒性反应的发生情况。结果正常情况下HDMTX匀速输注24 h完毕,允许误差±1 h(提前或延迟1 h),即药液持续输注23~25h属正常范围。注射泵组的HDMTX准时完成的例数明显高于输液泵组,两组间差异有显著性(P0.05),且前者的HDMTX输注实际完成时间与要求完成时间的差值明显低于后者(分别为0.50 h±0.28 h和1.90 h±1.11 h)(P0.05),注射泵组患者的HDMTX开始输注后24 h的血药浓度高于输注泵组(P0.05),而48 h的MTX血浆浓度却明显低于输液泵组(P0.05),且MTX相关毒性反应也明显低于后者(P0.05)。结论用注射泵通过PICC持续输注HDMTX更准确、有效和安全,既保证了疗效又显著降低了药物毒性反应,值得临床进一步推广。     

急性淋巴细胞性白血病患儿巯嘌呤耐受性研究

目的 调查急性淋巴细胞性白血病(acute lymphoblastie leukemia,ALL)患儿,维持化疗期间巯嘌呤(6-mercaptopurine,6-MP)的耐受性,为进一步研究6-MP耐受性差异的原因提供依据.方法 选择规范应用北京儿童医院急性淋巴细胞性白血病2003年化疗方案(BCH-ALL-2003),随访至2008年9月30日的患儿.全部患儿处于骨髓缓解期,且维持化疗≥13个月.详细记录患儿6-MP服用情况,包括服用剂量以及恶心、呕吐、皮疹等用药反应,以调查6-MP的耐受性.所有患儿每周复查血常规,间隔4周复查肝功能,并根据检查结果进行6-MP毒性分级.记录6-MP停止时间和剂量减少程度.结果共133例,男81例,女52例,中位年龄67个月(18～188个月),中位缓解时间26个月(6～47个月).6-MP维持化疗(13.5±7.4)个月(3～25个月),其中6-MP标准剂量、全疗程者72例(54%),剂量46 ms/(m~2·d),白细胞(WBC)(3～4)×10~9/L,中性粒细胞(ANC)(1.5～2.0)×10~9/L,肝脏毒性小于Ⅱ级,4例(3%)患儿ANC持续在3×10~9/L以上,6-MP剂量增加为标准剂量125%.余61例患儿均为严重不耐受6-MP者,其中骨髓抑制48例(同时伴肝毒性9例),单纯肝脏功能异常12例,反复皮疹1例.平均毒性反应出现时间为2.5周.19例患儿平均停用6-MP 7 d,42例患儿平均6-MP实际剂量25～30 ms/(m~2·d).结论 ALL患儿个体间6-MP的耐受性差异很大,46%ALL患儿对6-MP的标准治疗剂量表现为明显的骨髓抑制和肝功能异常等不耐受反应,临床需要根据血常规不断调整6-MP的剂量,以避免较大的毒性反应的发生,而3%患儿给予标准剂量6-MP,表现为无轻度骨髓抑制等化疗反应,临床需要增加6-MP剂量以减少复发危险性.但如何更准确地进行6-MP剂量调整是临床研究的难题之一.选择6-MP严重不耐受患儿进行6-MP代谢酶活性和基因多态性研究,以明确ALL儿童6-MP耐受性差异的原因,为进一步进行个体化药物剂量的调整提供理论依据.     

影响拉莫三嗪稳态血药浓度的相关因素研究

目的分析影响拉莫三嗪(LTG)稳态血药浓度的相关因素,探讨LTG血药浓度监测对癫治疗的重要性.方法应用LTG[(2.1±0.9)ng/kg]治疗3～14岁的癫患儿44例,测定其稳态血药浓度.应用逐步回归法分析影响LTG血药浓度的各类因素,并推算其有效治疗浓度.结果LTG血药浓度与剂量、体重、丙戊酸(VPA)的影响呈正相关(r分别为1.826、0.084、2.774,P均＜0.05),与年龄、卡马西平(CBZ)的影响呈负相关(r分别为-0.286、-2.382,P均＜0.05);性别与其则不存在显著的相关关系(P＞0.05).三组联合治疗组的血药浓度中位数(M)分别为0.75μg/nl(LTG+CBZ)、2.69μg/ml(LTG+VPA+CBZ)和3.42μg/ml(LTG+VPA),经H检验,各治疗组间差异有非常显著性(H=23.94,P＜0.01).21例(51.2%)治疗3个月后发作次数减少50%以上或完全控制发作,共测定LTG血药浓度27次,有效治疗浓度为3.09～5.90μg/ml,明显高于推荐范围的低限(1μg/ml).结论LTG稳态血药浓度可受年龄、体重、给药剂量、联合应用VPA或CBZ等因素的影响,故临床应用LTG治疗小儿癫,特别在多药联合治疗时,仅从给药剂量很难推测其血药浓度,有必要开展LTG血药浓度监测,以使治疗方案更具个体化.     

大剂量甲氨蝶呤治疗儿童急性淋巴细胞白血病79例毒副作用临床观察

目的观察大剂量甲氨蝶呤(HD-MTX)治疗儿童急性淋巴细胞白血病(ALL)所致毒副作用的临床特点。方法 79例ALL患儿按诊断标准分为标危组(MTX使用剂量为3g/m~2)和中高危组(MTX使用剂量为5g/m~2),接受HD-MTX治疗。在MTX开始36h后予亚叶酸钙解救,检测42~48h MTX血药浓度,同时观察患儿HD-MTX治疗后的毒副作用。结果 79例ALL患儿接受HD-MTX化疗后,发生中性粒细胞减少、血红蛋白降低和血小板减少的分别为52例(66%)、43例(54%)和10例(13%),发生肝脏毒性、黏膜损害和胃肠道反应者各为24例(30%)、29例(37%)和16例(20%),无一例发生肾脏毒性。42~48h MTX血药浓度与毒副作用的发生风险差异有显著性(P0.05)。比较标危组与中高危组MTX使用毒副作用的发生风险差异无显著性(P0.05)。结论 HD-MTX治疗ALL时毒副作用多为骨髓抑制、胃肠道反应、黏膜损害和肝脏毒性。毒副作用的发生与MTX血药浓度有关联,未发现使用3g/m~2和5g/m~2的MTX剂量与毒副作用的发生风险存在关联。     

Degradation and clearance of methotrexate in children with osteosarcoma receiving high-dose infusion.

Plasma methotrexate (MTX) concentrations were quantitated in 34 patients after 127 high-dose (35--350 mg/kg) infusions with citrovorum factor rescue. Significant linear correlations have been obtained between methotrexate dosage and concentrations in plasma at 6 and 24 hours after the initiation of the therapy. However, similar trends have not been observed when 48- and 72-hour samples were analyzed. Clinical toxicity was not serious when the methotrexate level in plasma was less than 4.5 X 10(-6) M at 48 hours after the start of a six-hour infusion in children. A minimal four-hour steady-state methotrexate plasma level can be maintained during a six-hour infusion. Children excrete methotrexate at a faster rate than adults; the half-life of MTX during the first phase of plasma clearance curve is one hour shorter in children. Urinary analyses have indicated that substantial methotrexate is metabolized. The chemical nature of these components has not been identified. Further, the urinary metabolic profiles varied among patients.     

Clinical significance of non-renal elimination mechanisms of methotrexate (MTX)

Biliary MTX levels in one patient undergoing intermediate dose MTX therapy (500 mg/m2) were measured by HPLC. At the end of the 24 h infusion period they were found in the range of the corresponding serum levels. In one other patients undergoing high-dose MTX therapy (12 g/m2) MTX serum levels in the slow elimination phase were lowered by orally applicated cholestyramine. In one further patient who developed renal failure under high-dose MTX therapy total body clearance of MTX could be markedly improved by cholestyramine per os. The data presented, suggesting an appreciable biliary secretion of the drug in man, are discussed in view of the current concepts of enterohepatic circulation of MTX.     

Methotrexate as relapse therapy for rhabdomyosarcoma

Four patients had a local relapse after standard therapy for rhabdomyosarcoma and were treated with high-dose 42-hour MTX infusions. All patients responded to this therapy, one patient had a complete, and two patients a partial remission. Long duration MTX infusion should be part of a combination chemotherapy for relapsed rhabdomyosarcomas.     

Degradation and clearance of methotrexate in children with osteosarcoma receiving high-dose infusion

Plasma methotrexate (MTX) concentrations were quantitated in 34 patients after 127 high-dose (35–350 mg/kg) infusions with citrovorum factor rescue. Significant linear correlations have been obtained between methotrexate dosage and concentrations in plasma at 6 and 24 hours after the initiation of the therapy. However, similar trends have not been observed when 48- and 72-hour samples were analyzed. Clinical toxicity was not serious when the methotrexate level in plasma was < 4.5 × 10^?6 M at 48 hours after the start of a six-hour infusion in children. A minimal four-hour steady-state methotrexate plasma level can be maintained during a six-hour infusion. Children excrete methotrexate at a faster rate than adults; the half-life of MTX during the first phase of plasma clearance curve is one hour shorter in children. Urinary analyses have indicated that substantial methotrexate is metabolized. The chemical nature of these components has not been identified. Further, the urinary metabolic profiles varied among patients.     

Retrospective study on elimination delay of methotrexate in high-dose therapy of childhood acute lymphoblastic leukemia in China

OBJECTIVES: The aim of this study was to observe the morbidity of elimination delay in Chinese children with acute lymphoblastic leukemia during high-dose methotrexate (HDMTX) therapy and the toxicities. PATIENTS AND METHODS: A total of 121 children with acute lymphoblastic leukemia on HDMTX therapy were enrolled into this study. Patients were divided into groups on the basis of either dosage (3 g/m vs. 5 g/m) or infusion duration (7 h vs. 24 h). CF/MTX index was used to determine the calcium folinate (CF) rescuing intensity and toxicity was evaluated according to World Health Organization criteria. RESULTS: The overall morbidity of elimination delay was 12.1% in a total of 497 infusions. Patients with elimination delay had lower platelet count (P<0.01) and greater cumulative CF rescuing intensity (P<0.001). In 3-g group, children with elimination delay experienced severer oral mucous membrane damage (P<0.05) than those without elimination delay, and postponement of following chemotherapy (P=0.001). No significant difference was found in morbidity of elimination delay between 3 and 5-g groups (P>0.05) or 7 and 24-hour infusion groups (P>0.05). The only raised adverse effect in 5-g group was gastrointestinal (P=0.003) as compared with 3-g group. The CF rescuing intensity of 5-g group without elimination delay was lower than that of the 3-g group (P<0.01). CONCLUSIONS: (1) HDMTX with 5 g/m is as safe as 3 g/m under adequate hydration and alkalization. Twenty-four-hour infusion is optimal. (2) Individualized dosing is necessary.     

大剂量甲氨蝶呤治疗急性淋巴细胞白血病

目的研究3g/m2和5g/m2甲氨蝶呤(MTX)治疗急性淋巴细胞白血病(ALL)的血、脑脊液MTX浓度和不良反应。方法ALL患儿43例共接受98例次MTX3g/(m2·次)或5g/(m2·次)治疗,对两剂量组进行MTX血药质量浓度、脑脊液浓度及不良反应比较。结果1.MTX44、66h血药质量浓度与23hMTX血药质量浓度明显相关(P<0.05);2.不同个体间及同一个体不同时间使用同一给药方案血药质量浓度、脑脊液浓度水平差异较大;3.两剂量组不良反应发生率无明显差异(P>0.05),骨髓抑制、肝功能损害的MTX血药质量浓度无明显差异(P>0.05)。结论对于标危、高危ALL分别采用3、5g/(m2·次)的剂量是合理的,无严重不良反应发生。     

Methotrexate levels and outcome in osteosarcoma

BACKGROUND: Peak serum concentrations of methotrexate (MTX) have been reported to correlate with outcome in osteosarcoma (OS). Modification of the MTX dose to achieve peak levels between 700 and 1,000 micromol/L has been recommended. The goal of the study was to assess whether there is a correlation between histologic necrosis of the tumor and/or prognosis with peak MTX serum concentration. PROCEDURE: Treatment included multi-agent adjuvant chemotherapy, including high-dose MTX (12 g/m2). Peak MTX levels were drawn following a 4-hr infusion. Histologic evaluation for percent necrosis was done at the time of definitive resection. RESULTS: The median peak MTX level (n = 52 patients) was 1,060 micromol/L (range: 410-4,700 micromol/L), with significant intra-patient and inter-patient variability. Fifty-eight percent of the levels were 1,000 micromol/L or higher. Response to pre-operative chemotherapy was: 18% Grade I necrosis, 35% Grade II, 31% Grade III, and 16% Grade IV. No significant association was found between the mean peak MTX levels and necrosis (P = 0.44). Event-free survival (EFS) for the 48 patients with non-metastatic disease at diagnosis was 76% at 4 years of follow-up, with no association between the mean peak MTX level and EFS (P = 0.24). CONCLUSIONS: The absence of a demonstrable correlation between peak MTX levels and histologic necrosis or EFS may suggest that most patients achieve therapeutic levels when MTX is given at a dose of 12 g/m(2). The significant degree of intra-patient variability in peak levels poses a dilemma for pharmacokinetic adjustment. Continued use of HD-MTX in all patients, rather than dose adapted therapy, may be justified.     

Monitoring high dose methotrexate therapy (HD MTX) in children with osteosarcoma and computer simulation using a pharmacokinetic model

The pharmacokinetics of methotrexate (MTX) was studied in 15 children with osteosarcoma, treated (54 courses) with high-dose methotrexate (8, 10 i 12 g/m2; 4 h i.v. infusion). Pharmacokinetic analysis was performed by standard non-compartmental methods and using two-compartment nonlinear model with coexistence of additional, parallel linear route of elimination from central compartment. The model was used for computer simulation and prognosis of the serum-level curve course depending on the simulated dosage, enhanced diuresis and simulated kidney or liver insufficiency during the dose individualization. The usage of the pharmacokinetic model for computer simulations may improve understanding of the MTX kinetics and can optimise dosage regimens for the next cycles of chemotherapy.     

High-dose methotrexate therapy (6-8 g/m2) in childhood malignancies: clinical tolerability and pharmacokinetics

Five children, ages 2.5 to 12 years (mean 6.2 years), with acute lymphoblastic leukemia or non-Hodgkin's lymphoma were given 22 courses of high-dose methotrexate (HD-MTX) therapy (6-8 g/m2/24 h). No serious clinical complications were encountered, but stomatitis occurred after three (14%) of the courses. First-phase elimination half-lives (t1/2(alpha)) of MTX and 7-hydroxy-methotrexate (7-OH-MTX) after 21 infusions were 2.7 +/- 0.4 h and 6.5 +/- 1.8 h (mean +/- SD). In one course (4.5%) there was delayed systemic MTX elimination, with first-phase elimination half-lives (t1/2(alpha] for MTX and 7-OH-MTX of 4.2 and 9.9 h, respectively, and second-phase elimination half-lives (t1/2(beta)) of 43 and 58 h. Significant decreases in white blood cell count, increases in serum creatinine, and increases in alanine aminotransferase and/or aspartate aminotransferase during the first 2-6 days were present in five (23%), three (14%), and six (27%) of the courses, respectively. The regimen was tolerated well by the children.