聚氧乙烯蓖麻油中口服紫杉醇的群体药代动力学。
Population pharmacokinetics of orally administered paclitaxel formulated in Cremophor EL.
作者信息
de Jonge Milly E, Huitema Alwin Dr, Schellens Jan Hm, Rodenhuis Sjoerd, Beijnen Jos H
机构信息
Department of Pharmacy & Pharmacology, the Netherlands Cancer Institute/Slotervaart Hospital, Amsterdam, the Netherlands.
出版信息
Br J Clin Pharmacol. 2005 Mar;59(3):325-34. doi: 10.1111/j.1365-2125.2004.02325.x.
AIM
The vehicle Cremophor EL (CrEL) has been shown to impair the absorption of paclitaxel by micellar entrapment of the drug in the gastrointestinal tract. The goal of this study was to develop a semimechanistic population pharmacokinetic model to study the influence of CrEL on the oral absorption of paclitaxel.
METHOD
Paclitaxel plasma-concentration time profiles were available from 55 patients (M:F, 17 : 38; total 67 courses; 797 samples), receiving paclitaxel orally once or twice daily (dose range 60-360 mg m(-2)) together with 12-15 mg kg(-1) cyclosporin A. A population pharmacokinetic model was developed using the nonlinear mixed effect modelling program NONMEM.
RESULTS
After absorption, paclitaxel pharmacokinetics were best described using a two-compartment model with linear distribution from the central compartment into a peripheral compartment and first-order elimination. Paclitaxel in the gastrointestinal tract was modelled as free fraction or bound to CrEL, with only the free fraction available for absorption into the central compartment. The equilibrium between free and bound paclitaxel was influenced by the concentration of CrEL present in the gastrointestinal tract. The concentration of CrEL in the gastrointestinal tract decreased with time with a first order rate constant of 1.73 h(-1). The bioavailability of paclitaxel was independent of the dose and of CrEL. Estimated apparent paclitaxel clearance and volume of distribution were 127 l h(-1) and 409 l, respectively. Large interpatient variability was observed. Covariate analysis did not reveal significant relationships with any of the pharmacokinetic parameters.
CONCLUSION
A pharmacokinetic model was developed that described the pharmacokinetics of orally administered paclitaxel. CrEL strongly influenced paclitaxel absorption from the gastrointestinal tract resulting in time-dependent but no significant dose-dependent absorption over the examined dose range studied.
目的
已证实辅料聚氧乙烯蓖麻油（CrEL）通过在胃肠道中胶束包裹药物而损害紫杉醇的吸收。本研究的目的是建立一个半机制群体药代动力学模型，以研究CrEL对紫杉醇口服吸收的影响。
方法
55例患者（男：女 = 17 : 38；共67个疗程；797个样本）的紫杉醇血浆浓度-时间曲线数据可用，这些患者每天口服一次或两次紫杉醇（剂量范围60 - 360 mg m⁻²），同时服用12 - 15 mg kg⁻¹环孢素A。使用非线性混合效应建模程序NONMEM建立群体药代动力学模型。
结果
吸收后，紫杉醇的药代动力学最好用二室模型描述，药物从中央室呈线性分布至周边室，并进行一级消除。胃肠道中的紫杉醇被建模为游离部分或与CrEL结合，只有游离部分可吸收进入中央室。游离和结合紫杉醇之间的平衡受胃肠道中CrEL浓度的影响。胃肠道中CrEL的浓度随时间以1.73 h⁻¹的一级速率常数下降。紫杉醇的生物利用度与剂量和CrEL无关。估计的紫杉醇表观清除率和分布容积分别为127 l h⁻¹和409 l。观察到患者间存在较大变异性。协变量分析未揭示与任何药代动力学参数的显著关系。
结论
建立了一个描述口服紫杉醇药代动力学的药代动力学模型。CrEL强烈影响紫杉醇从胃肠道的吸收，导致在所研究的剂量范围内吸收呈时间依赖性但无显著剂量依赖性。
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