甲氨蝶呤大剂量化疗的群体药动学研究

叶敏;付强;李鹏;朱珠

中国药学杂志 ›› 2009, Vol. 44 ›› Issue (05) : 367-372.

中国药学杂志 ›› 2009, Vol. 44 ›› Issue (05) : 367-372.
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甲氨蝶呤大剂量化疗的群体药动学研究

  • 叶敏;付强;李鹏;朱珠
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High Dose Methotrexate Population Pharmacokinetics and Bayesian Estimation in Patients with Lymphoid Malignancy

  • YE Min,FU Qiang,LI Peng,ZHU Zhu
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摘要

目的在淋巴瘤化疗患者中建立大剂量甲氨蝶呤(MTX)的群体药动学模型,评价病生理和临床因素对药物分布和消除的影响,并利用Bayesian方法预测药物浓度达到目标值(0.2μmol·L-1)所需要的时间。方法82名恶性淋巴瘤病人接受了大剂量甲氨蝶呤化疗并入组。利用NONMEM法建立药动学模型。考察病生理因素、临床合用药对药动学行为的影响。利用交错确认法和自举法对模型进行验证。结果大剂量甲氨蝶呤化疗符合二室模型分布特征。药动学参数及其个体间变异如下:清除率CL 7.45L·h-1(个体间变异51.4%),中心室表观分布容积V1 25.9L(22.4%),外周室分布容积V2 9.23L(42.3%),室间转运系数Q 0.333L·h-1(70.7%)。血清肌苷浓度对清除率、体重对表观分布容积表现出明显的影响。Bayesian方法能够预测给药后44h药物浓度及达到安全阈值(0.2μmol·L-1)所需要的时间。结论血清肌苷和体重分别对甲氨蝶呤体内清除率和表观分布容积有影响。利用Bayesian估计和44h药物浓度可以预测个体的药动学参数和达到0.2μmol·L-1所需要的时间。

Abstract

OBJECTIVE To develop a population pharmacokinetic model of high dose methotrexate(HD-MTX) infusion in patients with lymphoid malignancy,to investigate the biological and clinical covariates related to the drug distribution and elimination,and to propose a limited sampling strategy(LSS) for the estimation of the time above the threshold(0.2 μmol·L-1).METHODS A total 82 patients with lymphoid malignancy receiving high dose methotrexate treatment were involved in the study.A pharmacokinetic model was developed using nonlinear mixed-effect model.The influence of demographic characteristics,biological factors,and concurrent administration were investigated.The final predictive performance was validated by bootstrap and cross-validation.Bayesian estimation was evaluated.RESULTS The pharmacokinetics of high dose methotrexate were described by a two-compartment model.The pharmacokinetic parameters and the inter-individual variability were as follows:the clearance CL 7.45 L·h-1(inter-individual variability 51.4%),the volume of the central and peripheral compartment V1 25.9 L(22.4%),V2 9.23 L(42.3%),respectively,and the transfer constant Q 0.333 L·h-1(70.7%).The influence of serum creatinine on CL and weight on V1 was remained in the final model.The protocol involved one sampling time,44 h after the beginning of the infusion,allowed to predict the time at which the methotrexate concentration reached the expected threshold(0.2 μmol·L-1).CONCLUSION Serum creatinine and weight showed significant influence on methotrexate CL and V1,respectively.Furthermore,a Bayesian estimation based the covariates and 44 h sample was developed,allowing predict the individual methotrexate pharmacokinetic parameters and the time to 0.2 μmol·L-1.

关键词

群体药动学 / 甲氨蝶呤 / NONMEM / Bayesianestimation

Key words

population pharmacokinetics / methotrexate / NONMEM / Bayesian estimation

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导出引用
叶敏;付强;李鹏;朱珠. 甲氨蝶呤大剂量化疗的群体药动学研究[J]. 中国药学杂志, 2009, 44(05): 367-372
YE Min;FU Qing;LI Peng;ZHU Zhu. High Dose Methotrexate Population Pharmacokinetics and Bayesian Estimation in Patients with Lymphoid Malignancy [J]. Chinese Pharmaceutical Journal, 2009, 44(05): 367-372

参考文献

[1] SCHORNAGEL J H,MCVIE J G. The clinical pharmacology of methotrexate[J]. Cancer Treat Rev,1983,10(1):53-75. [2] PUI C H,EVANS W E. Treatment of acute lymphoblastic leukemia[J]. N Engl J Med,2006,354(2):166-178. [3] MANTADAKIS E,COLE P D,KAMEN B A. High-dose methotrexate in acute lymphoblastic leukemia:where is the evidence for its continued use? [J]. Pharmocotherapy,2005,25(5):748-755. [4] TAKAMI M,KUNIYOSHI Y,OOMUKAI T,et al. Severe complications after high-dose methotrexate treatment[J]. Acta Oncol,1995,34(5):611-612. [5] DE VITA V T,HELLMAN S,ROSENBERG S A. Cancer-Principles and Practice of Oncology[M]. Philadelphia:Lippincott. Williams &Wilkins,2005. [6] VAN DEN BONGARD H J,MATHOT R A,BEIJNEN J H,et al. Pharmacokinetically guided administration of chemotherapeutic agents[J]. Clin Pharmacokinet,2000,39(5):345-367. [7] FAVRE R,MONJANEL S,ALFONSI M,et al. High-dose methotrexate:a clinical and pharmacokinetic evaluation. Treatment of advanced squamous cell carcinoma of the head and neck using a prospective mathematical model and pharmacokinetic surveillance[J]. Cancer Chemother Pharmacol,1982,9(3):156-160. [8] RELLING M V,FAIRCLOUGH D,AYERS D,et al. Patient characteristics associated with high-risk methotrexate concentrations and toxicity[J]. J Clin Oncol,1994,12(8):1667-1672. [9] VINKS A A. The application of population pharmacokinetic modeling to individualized antibiotic therapy[J]. Int J Antimicrob Agents,2002,19(4):313-322. [10] KARLSSON M O. SHEINER L B. The importance of modeling interoccasion variability in population pharmacokinetic analyses[J]. J Pharmacokinet Biopharm,1993,21(6):735-750. [11] SHEINER L B,BEAL S L. Some suggestions for measuring predictive performance[J]. J Pharmacokinet Biopharm,1981,9(4):503-512. [12] PIARD C,BRESSOLLE F,FAKHOURY M,et al. A limited sampling strategy to estimate individual pharmacokinetic parameters of methotrexate in children with acute lymphoblastic leukemia[J]. Cancer Chemother Pharmacol,2007,60(4):609-620. [13] MONJANEL-MOUTERDE S,LEJEUNE C,CICCOLINI J,et al. Bayesian population model of methotrexate to guide dosage adjustments for folate rescue in patients with breast cancer[J]. J Clin Pharm Ther,2002,27(3):189-195. [14] ODOUL F,LE GUELLEC C,LAMAGNERE J P,et al. Prediction of methotrexate elimination after high dose infusion in children with acute lymphoblastic leukaemia using a population pharmacokinetic approach[J]. Fundam Clin Pharmacol,1999,13(5):595-604. [15] AUMENTE D,BUELGA D S,LUKAS J C,et al. Population pharmacokinetics of high-dose methotrexate in children with acute lymphoblastic leukaemia[J]. Clin Pharmacokinet,2006,45(12):1227-1238. [16] FALTAOS D W,HULOT J S,URIEN S,et al. Population pharmacokinetic study of methotrexate in patients with lymphoid malignancy[J]. Cancer Chemother Pharmacol,2006,58(5):626-633. [17] WANG Y M,SUTOW W W,ROMSDAHL M M,et al. Age-related pharmacokinetics of high-dose methotrexate in patients with osteosarcoma[J]. Cancer Treat Rep, 1979,63(3):405-410. [18] WIDEMANN B C,BALIS F M,KEMPF-BIELACK B,et al. High-dose methotrexate-induced nephrotoxicity in patients with osteosarcoma[J]. Cancer, 2004,100(10):2222-2232. [19] GRAF N,WINKLER K,BETLEMOVIC M,et al. Methotrexate pharmacokinetics and prognosis in osteosarcoma[J]. J Clin Oncol, 1994 ,12(7):1443-1451. [20] BRESSOLLE F,BOLOGNA C,KINOWSKI J M,et al. Effects of moderate renal insufficiency on pharmacokinetics of methotrexate in rheumatoid arthritis patients[J]. Ann Rheum Dis,1998,57(2):110-113. [21] SK?RBY T,J?NSSON P,HJORTH L,et al. High-dose methotrexate:on the relationship of methotrexate elimination time vs renal function and serum methotrexate levels in 1164 courses in 264 Swedish children with acute lymphoblastic leukaemia (ALL) [J]. Cancer Chemother Pharmacol,2003,51(4):311-320. [22] JOANNON P,OVIEDO I,CAMPBELL M,et al. High-dose methotrexate therapy of childhood acute lymphoblastic leukemia:lack of relation between serum methotrexate concentration and creatinine clearance[J]. Pediatr Blood Cancer,2004,43(1):17-22. [23] DUPUIS C,MERCIER C,YANG C,et al. High-dose methotrexate in adults with osteosarcoma:a population pharmacokinetics study and validation of a new limited sampling strategy[J]. Anticancer Drugs,2008,19(3):267-273. [24] EVANS W E,CHRISTENSEN M L. Drug interactions with methotrexate[J]. J Rheumatol,1985,12(Suppl 12):15-20. [25] FERRAZZINI G,KLEIN J,SULH H,et al. Interaction between trimethoprim-sulfamethoxazole and methotrexate in children with leukemia[J]. J Pediatr,1990,117(5):823-826.

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