Joerger Markus, Huitema Alwin D R, van den Bongard Desiree H J G, Schellens Jan H M, Beijnen Jos H
Department of Pharmacy and Pharmacology, Slotervaart Hospital, Amsterdam, The Netherlands.
Clin Cancer Res. 2006 Apr 1;12(7 Pt 1):2150-7. doi: 10.1158/1078-0432.CCR-05-2069.
The aim of this study was to quantitatively assess the effect of anthropometric and biochemical variables and third-space effusions on paclitaxel pharmacokinetics in solid tumor patients.
Plasma concentration-time data of paclitaxel were collected in patients with non-small cell lung cancer (n = 84), ovarian cancer (n = 40), and various solid tumors (n = 44), totaling 168 patients. Paclitaxel was given as a 3-hour infusion (n = 163) at doses ranging from 100 to 250 mg/m(2), or as a 24-hour infusion (n = 5) at a dose of 135 or 175 mg/m(2). Data were analyzed using nonlinear mixed-effect modeling.
A three-compartment model with saturable elimination and distribution was used to describe concentration-time data. Male gender and body surface area were positively correlated with maximal elimination capacity of paclitaxel (VM(EL)); patient age and total bilirubin were negatively correlated with VM(EL) (P < 0.005 for all correlations). Typically, male patients had a 20% higher VM(EL); a 0.2 m(2) increase of body surface area led to a 9% increase of VM(EL); a 10-year increase of patient age led to a 5% decrease of VM(EL); and a 10-micromol increase of total bilirubin led to a 14% decrease of VM(EL). Third-space effusions were not correlated with paclitaxel pharmacokinetics.
This extended retrospective population analysis showed patient gender to significantly and independently affect paclitaxel distribution and elimination. Body surface area, total bilirubin, and patient age were confirmed to affect paclitaxel elimination. This pharmacokinetic model allowed quantification of the covariate effects on the elimination of paclitaxel and may be used for covariate-adapted paclitaxel dosing.
本研究的目的是定量评估人体测量学和生化变量以及第三间隙积液对实体瘤患者紫杉醇药代动力学的影响。
收集了非小细胞肺癌患者（n = 84）、卵巢癌患者（n = 40）和各种实体瘤患者（n = 44）的紫杉醇血浆浓度-时间数据，共计168例患者。紫杉醇以100至250mg/m²的剂量进行3小时输注（n = 163），或以135或175mg/m²的剂量进行24小时输注（n = 5）。使用非线性混合效应模型分析数据。
采用具有饱和消除和分布的三室模型来描述浓度-时间数据。男性性别和体表面积与紫杉醇的最大消除能力（VM(EL)）呈正相关；患者年龄和总胆红素与VM(EL)呈负相关（所有相关性的P < 0.005）。通常，男性患者的VM(EL)高20%；体表面积增加0.2m²导致VM(EL)增加9%；患者年龄增加10岁导致VM(EL)降低5%；总胆红素增加10μmol导致VM(EL)降低14%。第三间隙积液与紫杉醇药代动力学无关。
这项扩展的回顾性人群分析表明患者性别对紫杉醇的分布和消除有显著且独立的影响。体表面积、总胆红素和患者年龄被证实会影响紫杉醇的消除。该药代动力学模型能够量化协变量对紫杉醇消除的影响，可用于根据协变量调整紫杉醇给药剂量。
