Phase I study of infusional paclitaxel in combination with the P-glycoprotein antagonist PSC 833
Phase I study of infusional paclitaxel in combination with the P-glycoprotein antagonist PSC 833
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DOI：
10.1200/jco.2001.19.3.832
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发表时间：
2001-02-01
影响因子：
45.3
通讯作者：
Bates, S
中科院分区：
文献类型：
--
作者：
Chico, I;Kang, MH;Bates, S
PSC 833（valspodar）是第二代P-糖蛋白（Pgp）拮抗剂，用于逆转多药耐药。我们进行了一项为期7天的口服PSC 833与紫杉醇联合给药的I期研究，作为96小时连续infus.Patients和方法：50例晚期癌症患者参加了试验。PSC 833口服给药7天，在紫杉醇输注开始前72小时开始，由于已知与PSC 833发生药代动力学相互作用，计划减少紫杉醇剂量。结果：与PSC 833联合使用时，最大耐受剂量定义为紫杉醇13.1 mg/m2/d连续静脉输注（CIVI）4天，不使用非格司亭，紫杉醇17.5 mg/m2/d，CIV 4天，并给予非格司亭支持。联合用药的剂量限制性毒性为中性粒细胞减少症。队列的统计分析显示，当患者接受13.1或17.5 mg/m（2）/d紫杉醇剂量持续4天并联合PSC 833时，平均稳态浓度（C-pss）和浓度-时间曲线下面积（AUC）与他们接受ct紫杉醇剂量35 mg/m（2）/d持续4天而不联合PSC 833时相似。然而，PSC 833对紫杉醇药代动力学的影响在个体患者中差异很大，尽管使用CD 56+细胞的替代试验表明在低浓度的PSC 833下Pgp的抑制是完全或几乎完全的。反应发生在四个非小细胞肺癌患者中的三个，发生在五个10例卵巢carcinoma.Conclusion：PSC 833与紫杉醇的组合可以安全地给药的患者提供紫杉醇剂量减少，以补偿药代动力学相互作用。使用CD 56+细胞的替代研究表明，PSC 833的最大耐受剂量产生的血清水平远高于阻断Pgp所需的水平。尽管在替代试验中完全抑制了Pgp，但紫杉醇药代动力学的变异性表明，其他机制（最可能与P450相关）有助于药代动力学相互作用。诸如此类的组合的未来开发应包括预测化疗剂的药代动力学的策略。这反过来将有助于给药以实现相当的CPss和AUC。(C)2001年，美国临床肿瘤学会。
Purpose: PSC 833 (valspodar) is a second-generation P-glycoprotein (Pgp) antagonist developed to reverse multidrug resistance. We conducted a phase I study of a 7-day oral administration of PSC 833 in combination with paclitaxel, administered as a 96-hour continuous infusion.Patients and Methods: Fifty patients with advanced cancer were enrolled onto the trial. PSC 833 was administered orally for 7 days, beginning 72 hours before the start of the paclitaxel infusion, Paclitaxel dose reductions were planned because of the pharmacokinetic interactions known to occur with PSC 833.Results: In combination with PSC 833, maximum-tolerated doses were defined as paclitaxel 13.1 mg/m(2)/d continuous intravenous infusion (CIVI) for 4 days without filgrastim, and paclitaxel 17.5 mg/m(2)/d CIVI for 4 days with filgrastim support. Dose-limiting toxicity for the combination was neutropenia. Statistical analysis of cohorts revealed similar mean steady-state concentrations (C-pss) and areas under the concentration-versus-time curve (AUCs) when patients received paclitaxel doses of 13.1 or 17.5 mg/m(2)/d for 4 days with PSC 833, as when they received ct paclitaxel dose of 35 mg/m(2)/d for 4 days without PSC 833. However, the effect of PSC 833 on paclitaxel pharmacokinetics varied greatly among individual patients, although a surrogate assay using CD56+ cells suggested inhibition of Pgp was complete or nearly complete at low concentrations of PSC 833. Responses occurred in three of four patients with non-small-cell lung cancer, and clinical benefit occurred in five of 10 patients with ovarian carcinoma.Conclusion: PSC 833 in combination with paclitaxel can be administered safely to patients provided the paclitaxel dose is reduced to compensate for the pharmacokinetic interaction. Surrogate studies with CD56+ cells indicate that the maximum-tolerated dose for PSC 833 gives serum levels much higher than those required to block Pgp. The variability in paclitaxel pharmacokinetics, despite complete inhibition of Pgp in the surrogate assay, suggests that other mechanisms, most likely related to P450, contribute to the pharmacokinetic interaction. Future development of combinations such as this should include strategies to predict pharmacokinetics of the chemotherapeutic agent, This in turn will facilitate dosing to achieve comparable CPss and AUCs. (C) 2001 by American Society of Clinical Oncology.