A pharmacodynamic study of docetaxel in combination with the P-glycoprotein antagonist tariquidar (XR9576) in patients with lung, ovarian, and cervical cancer.
A pharmacodynamic study of docetaxel in combination with the P-glycoprotein antagonist tariquidar (XR9576) in patients with lung, ovarian, and cervical cancer.
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DOI：
10.1158/1078-0432.ccr-10-1725
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发表时间：
2011-02-01
期刊：
影响因子：
--
通讯作者：
Bates SE
中科院分区：
文献类型：
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作者：
Kelly RJ;Draper D;Chen CC;Robey RW;Figg WD;Piekarz RL;Chen X;Gardner ER;Balis FM;Venkatesan AM;Steinberg SM;Fojo T;Bates SE
由于复杂的药代动力学相互作用和未能证明有意义的结果，P-糖蛋白(Pgp)拮抗剂的开发一直很困难。在这里，我们报告了一项药代动力学和药效学试验的结果，该试验使用了第三代、有效的、非竞争性的PGP抑制剂，Tariquidar(XR9576)，与多西紫杉醇联合使用。在第一个治疗周期中，多西紫杉醇(40 mg/m2)在第1天和第8天分别用药或不用药(150 Mg)后进行药代动力学评价。采用99mTC-Sestamibi扫描和CD56+单核细胞罗丹明外排试验评价Pgp的抑制作用。在随后的周期中，多西紫杉醇75 mg/m2，每三周服用150 mg替奎达。48名患者参加了这项试验。235个周期中非血液学3/4级毒性最小。Tariquidar可抑制Pgp介导的罗丹明从CD56+细胞外流，并减少99mTc-Sestamibi从肝脏的清除。在10名肺癌患者中，有8名患者可见病灶中的赛司他米摄取增加了12%至24%。在使用和不使用他奎达的配对比较中，多西紫杉醇的倾向性没有显著差异。4例PR(4/48)，3例在非小细胞肺癌(NSCLC)队列中，RECIST分别为40%、57%和67%，1例卵巢癌患者PR。与以前的Pgp拮抗剂相比，Tariquidar的耐受性很好，观察到的全身药代动力学相互作用较少。Tariquidar对可成像肺癌患者Sestamibi滞留的不同影响表明，评估这一患者群体的肿瘤药物摄取情况的后续研究将是值得的。
P-glycoprotein (Pgp) antagonists have been difficult to develop because of complex pharmacokinetic interactions and a failure to demonstrate meaningful results. Here we report the results of a pharmacokinetic and pharmacodynamic trial using a third generation, potent, non-competitive inhibitor of Pgp, tariquidar (XR9576), in combination with docetaxel. In the first treatment cycle, the pharmacokinetics of docetaxel (40 mg/m2) were evaluated after day 1 and day 8 doses, which were administered with or without tariquidar (150 mg). 99mTc-sestamibi scanning and CD56+ mononuclear cell rhodamine efflux assays were performed to assess Pgp inhibition. In subsequent cycles, 75 mg/m2 docetaxel was administered with 150 mg tariquidar every three weeks. Forty-eight patients were enrolled onto the trial. Non-hematologic grade 3/4 toxicities in 235 cycles were minimal. Tariquidar inhibited Pgp-mediated rhodamine efflux from CD56+ cells and reduced 99mTc-sestamibi clearance from the liver. A 12 to 24% increase in sestamibi uptake in visible lesions was noted in 8 of 10 patients with lung cancer. No significant difference in docetaxel disposition was observed in pairwise comparison with and without tariquidar. Four PRs were seen (4/48); three in the non-small cell lung cancer (NSCLC) cohort, measuring 40%, 57% and 67% by RECIST and one PR in a patient with ovarian cancer. Tariquidar is well-tolerated with less observed systemic pharmacokinetic interaction than previous Pgp antagonists. Variable effects of tariquidar on retention of sestamibi in imageable lung cancers suggest that follow-up studies assessing tumor drug uptake in this patient population would be worthwhile.