Population pharmacokinetics of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (Triapine®) in cancer patients.
Population pharmacokinetics of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (Triapine®) in cancer patients.
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DOI：
10.1007/s00280-010-1331-z
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发表时间：
2011-02
影响因子：
3
通讯作者：
Wilding, George
中科院分区：
文献类型：
--
作者：
Kolesar, Jill;Brundage, Richard C.;Pomplun, Marcia;Alberti, Dona;Holen, Kyle;Traynor, Anne;Ivy, Percy;Wilding, George
关键词：
本研究的目的是建立3-AP药代动力学的群体药代动力学（PK）模型，评估ABCB1多态性对3-AP药代动力学的影响，并评估3AP倾向与患者协变量之间的关系。共有40名来自两项i期研究的晚期癌症患者被纳入人群PK模型构建。患者在第1天给予3-AP 25-105 mg/m2静脉注射。在24小时内的10个时间点采样3-AP血浆和红细胞水平，并通过有效的HPLC方法测量。数据分析采用非线性混合效应建模方法，采用NONMEM系统。3AP药代动力学描述为一阶消除的3室模型。一个室代表血浆，另一个室代表红细胞浓度。性别与体积分布有关，女性的V2值较低。给药周期数与清除率相关；清除率降低的患者更有可能在结束研究前接受少于2个疗程的治疗。本研究表明，在第一周期监测3-AP血浆浓度并对清除率降低的患者进行剂量调整可能有助于降低3-AP相关的毒性。
The purpose of this study was to develop a population pharmacokinetic (PK) model for 3-AP pharmacokinetics and to evaluate the effect of ABCB1 polymorphisms on the pharmacokinetic profile of 3-AP and to assess the relationship between 3AP disposition and patient covariates. A total of 40 patients with advanced cancer from two phase 1 studies were included in the population PK model building. Patients received 3-AP 25–105 mg/m2 IV on day 1. 3-AP plasma and erythrocyte levels were sampled at 10 timepoints over a 24-hour period and measured by a validated HPLC method. Data were analyzed by a nonlinear mixed-effects modeling approach using the NONMEM system. 3AP pharmacokinetics were described as a 3-compartment model with first-order elimination. One compartment representing the plasma and another representing erythrocyte concentrations. Gender was associated with volume of distribution, in which women had a lower V2. The number of cycles administered was associated with clearance; those with decreased clearance were more likely to receive less than 2 cycles before going off study. This study suggests that monitoring 3-AP plasma concentrations in the first cycle and dose adjustment in those with decreased clearance may be helpful in decreasing toxicity associated with the 3-AP.
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DOI：
10.1016/j.bbapap.2009.02.014
发表时间：
2009-05
期刊：
Biochimica et biophysica acta
影响因子：
--
作者：
Fung KL;Gottesman MM
通讯作者：
Gottesman MM
影响因子：
5.8
作者：
Mathijssen, Ron H. J.;De Jong, Floris A.;Sparreboom, Alex
通讯作者：
Sparreboom, Alex
影响因子：
5.8
作者：
Rappa, G;Lorico, A;Sartorelli, AC
通讯作者：
Sartorelli, AC
影响因子：
3.9
作者：
Kolesar, Jill M.;Schelman, William R.;Antholine, William E.
通讯作者：
Antholine, William E.
影响因子：
3.4
作者：
Knox, Jennifer J.;Hotte, Sebastien J.;Eisenhauer, Elizabeth A.
通讯作者：
Eisenhauer, Elizabeth A.