Phase I study of pegylated liposomal doxorubicin and the multidrug-resistance modulator, valspodar
Phase I study of pegylated liposomal doxorubicin and the multidrug-resistance modulator, valspodar
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DOI：
10.1038/sj.bjc.6602653
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发表时间：
2005-07-11
影响因子：
8.8
通讯作者：
McLeod, HL
中科院分区：
文献类型：
--
作者：
Fracasso, PM;Blum, KA;McLeod, HL
伐司泊达是一种P-糖蛋白调节剂，联合给药时会影响多柔比星的药代动力学，导致多柔比星剂量减少。在动物模型中，伐司泊达与聚乙二醇化脂质体多柔比星（PEG-LD）的相互作用极小。为了确定人体中的任何药代动力学相互作用，我们设计了一项研究，以确定PEG-LD和伐司泊达联合治疗晚期恶性肿瘤患者中总多柔比星的最大耐受剂量、剂量限制性毒性（DLT）和药代动力学。患者接受PEG-LD 20-25 mg m（-2）静脉注射1 h，第1周期。在随后的2周周期中，戊司泊达与PEG-LD以72小时连续静脉输注给药，起始剂量为8 mg m（-2），并以加速滴定设计递增至25 mg m（-2）。收集了使用和不使用伐司泊达的药代动力学数据。共有14例患者完成了至少两个周期的治疗。在接受最高水平PEG-LD 25 mg m（-2）治疗的6例患者中未观察到DLT。最常见的毒性反应为疲乏、恶心、呕吐、粘膜炎、掌跖红斑、腹泻和共济失调。在乳腺癌和卵巢癌患者中观察到部分缓解。平均（范围）总阿霉素清除率从第1周期的27（10-73）ml h（-1）m（-2）降至第2周期加用伐司泊达后的18（3-37）ml h（-1）m（-2）（P = 0.009）。PEG-LD 25 mg m（-2）与伐司泊达联合治疗可适度延长多柔比星的总清除率和半衰期，但不会增加该药物的毒性。
Valspodar, a P-glycoprotein modulator, affects pharmacokinetics of doxorubicin when administered in combination, resulting in doxorubicin dose reduction. In animal models, valspodar has minimal interaction with pegylated liposomal doxorubicin (PEG-LD). To determine any pharmacokinetic interaction in humans, we designed a study to determine maximum tolerated dose, dose-limiting toxicity (DLT), and pharmacokinetics of total doxorubicin, in PEG-LD and valspodar combination therapy in patients with advanced malignancies. Patients received PEG-LD 20-25 mg m(-2) intravenously over 1 h for cycle one. In subsequent 2-week cycles, valspodar was administered as 72 h continuous intravenous infusion with PEG-LD beginning at 8 mg m(-2) and escalated in an accelerated titration design to 25 mg m(-2). Pharmacokinetic data were collected with and without valspodar. A total of 14 patients completed at least two cycles of therapy. No DLTs were observed in six patients treated at the highest level of PEG-LD 25 mg m(-2). The most common toxicities were fatigue, nausea, vomiting, mucositis, palmar plantar erythrodysesthesia, diarrhoea, and ataxia. Partial responses were observed in patients with breast and ovarian carcinoma. The mean ( range) total doxorubicin clearance decreased from 27 (10-73) ml h(-1) m(-2) in cycle 1 to 18 (3-37) ml h(-1) m(-2) with the addition of valspodar in cycle 2 (P = 0.009). Treatment with PEG-LD 25 mg m(-2) in combination with valspodar results in a moderate prolongation of total doxorubicin clearance and half-life but did not increase the toxicity of this agent.