在新型P-糖蛋白调节剂盐酸佐苏喹达（LY335979）存在的情况下，紫杉醇的群体药代动力学模型。
A population pharmacokinetic model for paclitaxel in the presence of a novel P-gp modulator, Zosuquidar Trihydrochloride (LY335979).
作者信息
Callies Sophie, de Alwis Dinesh P, Harris Adrian, Vasey Paul, Beijnen Jos H, Schellens Jan H, Burgess Michael, Aarons Leon
机构信息
Eli Lilly and Company Limited, Windlesham, Surrey, UK.
出版信息
Br J Clin Pharmacol. 2003 Jul;56(1):46-56. doi: 10.1046/j.1365-2125.2003.01826.x.
AIMS
To develop a population pharmacokinetic model for paclitaxel in the presence of a MDR modulator, zosuquidar 3HCl.
METHODS
The population approach was used (implemented with NONMEM) to analyse paclitaxel pharmacokinetic data from 43 patients who received a 3-h intravenous infusion of paclitaxel (175 mg x m(-2) or 225 mg x m(-2)) alone in cycle 2 or concomitantly with the oral administration of zosuquidar 3HCl in cycle 1.
RESULTS
The structural pharmacokinetic model for paclitaxel, accounting for the Cremophor ELTM impact, was a three-compartment model with a nonlinear model for paclitaxel plasma clearance (CL), involving a linear decrease in this parameter during the infusion and a sigmoidal increase with time after the infusion. The final model described the effect of Zosuquidar 3HCl on paclitaxel CL by a categorical relationship. A 25% decrease in paclitaxel CL was observed, corresponding to an 1.3-fold increase in paclitaxel AUC (from 14829 microg x l(-1) x h to 19115 microg x l(-1) x h following paclitaxel 175 mg x m(-2)) when zosuquidar Cmax was greater than 350 microg x l(-1). This cut-off concentration closely corresponded to the IC50 of a sigmoidal Emax relationship (328 microg x l(-1)). A standard dose of 175 mg x m(-2) of paclitaxel could be safely combined with doses of zosuquidar 3HCl resulting in plasma concentrations known, from previous studies, to result in maximal P-gp inhibition.
CONCLUSIONS
This analysis provides a model which accurately characterized the increase in paclitaxel exposure, which is most likely to be due to P-gp inhibition in the bile canaliculi, in the presence of zosuquidar 3HCl (Cmax > 350 microg x l(-1)) and is predictive of paclitaxel pharmacokinetics following a 3 h infusion. Hence the model could be useful in guiding therapy for paclitaxel alone and also for paclitaxel administered concomitantly with a P-gp inhibitor, and in designing further clinical trials.
目的
建立在多药耐药调节剂盐酸唑苏喹达存在情况下紫杉醇的群体药代动力学模型。
方法
采用群体方法（用NONMEM软件实现）分析43例患者的紫杉醇药代动力学数据，这些患者在第2周期单独接受3小时静脉输注紫杉醇（175mg·m⁻²或225mg·m⁻²），或在第1周期同时口服盐酸唑苏喹达。
结果
考虑到聚氧乙烯蓖麻油ELTM影响的紫杉醇结构药代动力学模型是一个三室模型，其中紫杉醇血浆清除率（CL）采用非线性模型，该参数在输注期间呈线性下降，输注后随时间呈S形增加。最终模型通过分类关系描述了盐酸唑苏喹达对紫杉醇CL的影响。当盐酸唑苏喹达的Cmax大于350μg·L⁻¹时，观察到紫杉醇CL降低25%，这对应于紫杉醇AUC增加1.3倍（紫杉醇175mg·m⁻²后，从14829μg·L⁻¹·h增加到19115μg·L⁻¹·h）。该截断浓度与S形Emax关系的IC50（328μg·L⁻¹）密切对应。标准剂量175mg·m⁻²的紫杉醇可以安全地与盐酸唑苏喹达剂量联合使用，这些剂量会导致血浆浓度达到先前研究已知的能产生最大P-糖蛋白抑制作用的浓度。
结论
该分析提供了一个模型，该模型准确地描述了在盐酸唑苏喹达（Cmax>350μg·L⁻¹）存在时紫杉醇暴露的增加，这很可能是由于胆小管中P-糖蛋白受到抑制所致，并且可以预测3小时输注后紫杉醇的药代动力学。因此，该模型可用于指导单独使用紫杉醇以及与P-糖蛋白抑制剂联合使用紫杉醇的治疗，并用于设计进一步的临床试验。
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