CYP3A4*22 genotype and systemic exposure affect paclitaxel-induced neurotoxicity.
CYP3A4*22 genotype and systemic exposure affect paclitaxel-induced neurotoxicity.
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DOI：
10.1158/1078-0432.ccr-12-3786
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发表时间：
2013-06-15
期刊：
影响因子：
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通讯作者：
van Schaik RH
中科院分区：
文献类型：
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作者：
de Graan AJ;Elens L;Sprowl JA;Sparreboom A;Friberg LE;van der Holt B;de Raaf PJ;de Bruijn P;Engels FK;Eskens FA;Wiemer EA;Verweij J;Mathijssen RH;van Schaik RH
紫杉醇用于治疗几种实体瘤，并在暴露和毒性方面显示出较高的个体间差异。神经毒性是紫杉醇最突出的副作用之一。本研究探讨了神经毒性发作和严重程度的潜在预测药代动力学和药物遗传学决定因素。在接受紫杉醇治疗的探索性患者队列（n=261）中，确定了神经毒性发生率和严重程度、药代动力学参数和药物遗传学变异。通过HPLC或LC-MS/MS测量紫杉醇血浆浓度，并通过非线性混合效应模型（NONMEM）根据先前开发的群体药代动力学模型估计个体药代动力学参数。检测的紫杉醇药代动力学的遗传变异体为CYP 3A 4 *22、CYP 2C 8 *3、CYP 2C 8 *4和ABCB 1 3435 C>T。在一个独立的患者队列（n=239）中验证了探索性队列中观察到的CYP 3A 4 *22与神经毒性之间的相关性。紫杉醇暴露（logAUC）与神经毒性的严重程度相关（P <0.00001）。在探索性队列中，女性CYP 3A 4 *22携带者发生神经毒性的风险增加（P = 0.043）。CYP 3A 4 *22携带状态本身与男性或女性中紫杉醇的药代动力学参数（CL、AUC、Cmax或T>0.05）无关。其他遗传变异与神经毒性无关。在随后的独立验证队列中，CYP 3A 4 *22携带者有发生3级神经毒性的风险（比值比= 19.1; P = 0.001）。紫杉醇暴露与紫杉醇诱导的神经毒性的严重程度相关。在这项研究中，女性CYP 3A 4 *22携带者在紫杉醇治疗期间发生重度神经毒性的风险增加。这些观察结果可能指导未来的紫杉醇治疗的个体化。
Paclitaxel is used for the treatment of several solid tumors and displays a high inter-individual variation in exposure and toxicity. Neurotoxicity is one of the most prominent side-effects of paclitaxel. This study explores potential predictive pharmacokinetic and pharmacogenetic determinants for the onset and severity of neurotoxicity. In an exploratory cohort of patients (n=261) treated with paclitaxel, neurotoxicity incidence and severity, pharmacokinetic parameters and pharmacogenetic variants were determined. Paclitaxel plasma concentrations were measured by HPLC or LC-MS/MS, and individual pharmacokinetic parameters were estimated from previously developed population pharmacokinetic models by non-linear mixed effects modeling (NONMEM). Genetic variants of paclitaxel pharmacokinetics tested were CYP3A4*22, CYP2C8*3, CYP2C8*4, and ABCB1 3435 C>T. The association between CYP3A4*22 and neurotoxicity observed in the exploratory cohort was validated in an independent patient cohort (n=239). Exposure to paclitaxel (logAUC) was correlated with severity of neurotoxicity (P <0.00001). Female CYP3A4*22 carriers were at increased risk of developing neurotoxicity (P = 0.043) in the exploratory cohort. CYP3A4*22 carrier status itself was not associated with pharmacokinetic parameters (CL, AUC, Cmax, or T>0.05) of paclitaxel in males or females. Other genetic variants displayed no association with neurotoxicity. In the subsequent independent validation cohort, CYP3A4*22 carriers were at risk of developing grade 3 neurotoxicity (odds ratio = 19.1; P = 0.001). Paclitaxel exposure showed a relationship with the severity of paclitaxel-induced neurotoxicity. In this study, female CYP3A4*22 carriers had increased risk of developing severe neurotoxicity during paclitaxel therapy. These observations may guide future individualization of paclitaxel treatment.