A phase I trial of liposomal doxorubicin, paclitaxel and valspodar (PSC-833), an inhibitor of multidrug resistance
A phase I trial of liposomal doxorubicin, paclitaxel and valspodar (PSC-833), an inhibitor of multidrug resistance
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DOI：
10.1093/annonc/mdi396
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发表时间：
2005-12-01
影响因子：
50.5
通讯作者：
Sikic, BI
中科院分区：
文献类型：
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作者：
Advani, R;Lum, BL;Sikic, BI
目的：本研究的目的是确定(i)多柔比星（L-DOX）和紫杉醇（DP）的最大耐受剂量（MTD）， （ii） DP +缬斯波达（DPV）的MTD， （iii）缬斯波达与L-DOX和紫杉醇的药代动力学（PK）相互作用。方法：23例转移性肿瘤患者接受DP治疗，4周后再进行DPV治疗。L-DOX/紫杉醇DP剂量水平（mg/m(2)）： 30/135 （n = 7）、30/150 （n = 4）、35/150 （n = 8）和40/150 （n = 4）。DPV的剂量水平分别为15/70 （n = 10）和15/60 （n = 10）。进行了连续、配对的PK研究。结果：DP的MTD为40/150。对于DPV为15/70的患者，10名患者中有5名出现4级中性粒细胞减少症。在下一个队列中，减少的15/60的剂量耐受性良好。Valspodar在7例患者中产生可逆的3级共济失调，需要将剂量减少5 - 4mg /kg。配对PK研究表明L-DOX和valspodar之间没有相互作用，紫杉醇的中位半衰期增加49%。2例部分缓解，1例轻微缓解。结论：使用缬索达需要减少DP的剂量，中性粒细胞减少是剂量限制。Valspodar与紫杉醇有相互作用，但与L-DOX无相互作用。
Purpose: The aim of this study was to determine (i) the maximum tolerated dose (MTD) of liposomal doxorubicin (L-DOX) and paclitaxel (DP), (ii) the MTD of DP plus valspodar (DPV) and (iii) pharmacokinetic (PK) interactions of valspodar with L-DOX and paclitaxel.Methods: Twenty-three patients with metastatic cancers received DP, followed 4 weeks later by DPV. Dose levels of DP were (mg/m(2) for L-DOX/paclitaxel): 30/135 (n = 7), 30/150 (n = 4), 35/150 (n = 8) and 40/150 (n = 4). Dose levels of DPV were 15/70 (n = 10) and 15/60 (n = 10). Serial, paired PK studies were performed.Results: The MTD of DP was 40/150. For DPV at 15/70, five of 10 patients experienced grade 4 neutropenia. In the next cohort, a reduced dose of 15/60 was well tolerated. Valspodar produced reversible grade 3 ataxia in seven patients, requiring dose reduction from 5 to 4 mg/kg. Paired PK studies indicated no interaction between L-DOX and valspodar, and a 49% increase in the median half-life of paclitaxel. Two partial and one minor remissions were noted.Conclusions: The use of valspodar necessitated dose reductions of DP, with neutropenia being dose limiting. Valspodar PK interactions were observed with paclitaxel but not L-DOX.