淋巴系恶性肿瘤患儿5g/m^2氨甲蝶呤的群体药动学研究  

Population pharmacokinetics of high-dose methotrexate in childhood lymphoid malignancies

作　　者：刘玲[1] 华瑛[1] 赵卫红[1] 卢新天[1] 马岳红[1] 卢薇薇[1] 杜军保[1] 卢炜[2] 

机构地区：[1]北京大学第一医院儿科,北京100034 [2]北京大学医学部药学院,北京100191

出　　处：《中国实用儿科杂志》2011年第2期104-107,共4页Chinese Journal of Practical Pediatrics

摘　　要：目的建立大剂量氨甲蝶呤(HDMTX)5g/m2持续24h输注的群体药动学模型,获得模型参数群体值,用该模型分析HDMTX排泄延迟患儿的药动学特点。方法研究对象为2004年5月至2010年3月在北京大学第一医院儿科血液病房的51例淋巴系恶性肿瘤患儿,所有患儿接受HDMTX5g/m2持续输注24h,共194疗程。在输注的不同时间采集外周静脉血,测定MTX血药浓度,应用NONMEM软件建立HDMTX5g/m2持续24h输注的群体药动学模型,根据建立的模型估算患儿MTX代谢参数的群体值,并运用模型分析排泄延迟患儿药动学参数特点。结果 HDMTX5g/m2持续输注24h在淋巴恶性肿瘤患儿体内符合二室一级消除模型,全身清除率CL1=5.61×[1-0.0183×(Age-8.3)+0.00683×(WBC-7.12)]L(/h·m2),室间清除率CL2=0.239L(/h·m2),中央室表观分布容积V1=12.1×[1+0.0369×(BUN-3.52)]L/m2,周围室表观分布容积V2=2.83×(1+0.00102×(PLT-254.6))L/m2。分布相常数α平均值为0.469(0.14～1.96)L/h,消除相常数β平均值为0.104(0.02～0.3)L/h。分布相半衰期t1/2α平均值为1.654(0.35～5.08)h,消除相半衰期t1/2β平均值为8.827(2.29～28.56)h,经过7个分布相半衰期之后药物进入消除相。排泄延迟组的CL2和V2均明显大于无排泄延迟组。结论患儿外周血WBC对CL1、血浆BUN对V1、PLT对V2在一定范围内可能有影响。在HDMTX5g/m2持续输注过程中,发生排泄延迟组药物其药物更多分布于周围室。根据建立的群体药物代谢学模型可以推测不同时间的MTX浓度,来更好地指导解救,降低排泄延迟时毒副作用的发生。Objective To establish the population pharmacokinetic model of high-dose methotrexate （HDMTX）5 g/m^2 in children with lymphoid malignancies, and evaluate characteristics of pharmacokinetic parameters about the elimination delay of HDMTX 5 g/m^2 . Methods Fifty-one children with lymphoid malignancies received 194 courses of HDMTX 5 g/ m^2. Measure MTX in plasma by FPIA. An extended least squares approach to nonlinear mixed effects modeling （NONMEM） was used to estimate pharmacokinetic parameters, intersubject and residual variability. Explain this variability in terms of palient specific information such as age or body weight and so on. Evaluate characteristics of pharmacokinetie parameters about the elimination delay of HDMTX 5g/m^2. Results The following population parameters were obtained using a two-compartment open model. Clearance of central compartment （CL1）= 5.61 x （1 - 0.0183 x （Age-8.3） ＋ 0.00683 ×（WBC-7.12） ） L/（h· m^2）, inter-compartment clearance （CL2） = 0.239 L/（h· m^2）, central volume （V1）= 12.1 × （1 ＋ 0.0369 ×（BUN-3.52））L/m^2,perilpheral volume（V2）=2.83 × （1 ＋ 0.00102 × （PLT-254.6））L/ m^2. The constant of distribution phase was α , the average being 0.469/h, ranging from 0.14/h to 1.96/h.The constant of elimination phase was 13 , the average being 1.645/h, ranging from 0.02/h to 0.3/h. The elimination phase started 7 distribution phases laler. Both the inter-compartment clearance and the peripheralvolume of the elimination delay group volume. There might be more MTX distributing to the peripheral volume, if elimination delay happened. As a result of rescue based on the measurement of MTX concentration in plasma, the toxicity effect of elimination delay group could be controlled.

关 键 词：儿童 淋巴系恶性肿瘤 大剂量氨甲蝶呤 群体药动学 

分 类 号：R72[医药卫生—儿科]