Association of paclitaxel pharmacokinetics with the development of peripheral neuropathy in patients with advanced cancer

被引:105
作者
Mielke, S
Sparreboom, A
Steinberg, SM
Gelderblom, H
Unger, C
Behringer, D
Mross, K
机构
[1] Univ Freiburg, Med Ctr, Dept Hematol & Oncol, D-7800 Freiburg, Germany
[2] Univ Freiburg, Tumor Biol Ctr, Freiburg, Germany
[3] NCI, Ctr Canc Res, Biostat & Data Management Sect, NIH, Bethesda, MD 20892 USA
[4] NCI, Clin Pharmacol Res Core, Bethesda, MD 20892 USA
[5] Dr Daniel Den Hoed Canc Ctr, Dept Med Oncol, Erasmus MC, NL-3008 AE Rotterdam, Netherlands
[6] Leiden Univ, Med Ctr, Dept Med Oncol, Leiden, Netherlands
关键词
D O I
10.1158/1078-0432.CCR-05-0298
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Purpose:The shortening of infusion time from 3 to 1 hour decreases the systemic exposure (area under the curve, AUC) of total and unbound paclitaxel but increases the AUC of its vehicle Cremophor EL, whereas the time above total paclitaxel concentrations of 0.05 mu mol/L (T-> 0.05) remains almost constant. As both Cremophor EL and paclitaxel are neurotoxic, we evaluated their pharmacodynamic effects on the development of peripheral neuropathy as the most important nonhematologic toxicity. Experimental Design: Patients with advanced cancer of different origin were randomized to receive a maximum of 12 weekly-given 1- or 3-hour infusions of 100 mg/m(2) paclitaxel (Taxol). Twenty-four patients were assessable for both pharmacokinetics and peripheral neuropathy development evaluated by a clinical scoring system including sensory symptoms, strength, tendon reflexes, and vibratory sense. Results: Patients with peripheral neuropathy development (n = 14) received more weeks of therapy (P = 0.056) and showed significantly higher T-> 0.05 (P = 0.022) and overall systemic drug exposures (weeks of therapy x AUC) for total paclitaxel (P = 0.002) and unbound paclitaxel (P = 0.003) than those without peripheral neuropathy. In Kaplan-Meier analyses, T-> 0.05 >= 10.6 hours (P = 0.023), AUC of total paclitaxel >= 4.7 mu g/mL x hour (P = 0.047), and AUC of unbound paclitaxel >= 0.375 mu g/mL x hour (P = 0.095) were identified as being potential factors for peripheral neuropathy development. In a Cox regression analysis, only T-> 0.05 >= 10.6 hours remained as an independent risk factor (relative risk, 18.43; P = 0.036) after adjusting for prior vincamycin (relative risk, 11.28; P = 0.038). Conclusions: From the results obtained in this study, it is concluded that exposure to paclitaxel but not Cremophor EL is associated with peripheral neuropathy development.
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页码:4843 / 4850
页数:8
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