Phase I and pharmacokinetic trial of paclitaxel in patients with hepatic dysfunction: Cancer and Leukemia Group B 9264
Phase I and pharmacokinetic trial of paclitaxel in patients with hepatic dysfunction: Cancer and Leukemia Group B 9264
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DOI：
10.1200/jco.1998.16.5.1811
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发表时间：
1998-05-01
影响因子：
45.3
通讯作者：
Schilsky, RL
中科院分区：
文献类型：
--
作者：
Venook, AP;Egorin, MJ;Schilsky, RL
目的：明确肝功能异常患者使用紫杉醇的最大耐受剂量、剂量限制性毒性（DLT）以及药代动力学特征。
患者与方法：患有适合紫杉醇治疗的肿瘤且肝功能检查异常的成年患者符合入选条件。患者被分配到三个治疗队列中的一个：队列I，天冬氨酸氨基转移酶（AST）水平为正常的两倍且胆红素水平低于1.5 mg/dL；队列II，胆红素水平为1.6 - 3.0 mg/dL；队列III，胆红素水平高于3.0 mg/dL。在每个队列中至少对3名患者探索剂量。尽管试验设计是评估24小时输注方案，但也扩展到评估3小时给药方案。对所有患者都要进行药代动力学研究。
结果：81名患者可进行毒性评估。胆红素水平高于1.5 mg/dL的患者在所有探索的剂量下都有明显毒性，而AST水平升高的患者在24小时内给药剂量为50 - 175 mg/m²时出现毒性。在大多数患者中，剂量限制性毒性是骨髓抑制。药代动力学数据不足以充分评估24小时输注患者的药代动力学与毒性之间的关系，但在3小时输注组中提供了证据，表明紫杉醇的暴露时间比本研究中使用的剂量预期的要长。
结论：如果对AST或胆红素水平升高的患者使用紫杉醇，有必要降低剂量，并且可以预期毒性会增加。观察到的骨髓抑制增加至少部分是由于此类患者紫杉醇药代动力学改变所致。（C）1998年美国临床肿瘤学会
Purpose: To characterize the maximum-tolerated dose, dose-limiting toxicities (DLTs), and pharmacokinetics of paclitaxel in patients with abnormal liver function.Patients and Methods: Adults with tumors appropriate for paclitaxel therapy who herd abnormal liver function tests were eligible. Patients were assigned to one of three treatment cohorts: I, AST level twofold normal and bilirubin level less than 1.5 mg/dL; II, bilirubin level 1.6 to 3.0 mg/dL; and III, bilirubin level greater than 3.0 mg/dL, Doses were explored in at least three patients within each cohere, Although designed to assess a 24-hour infusion schedule, the trial was extended to also assess a 3-hour regimen. Pharmacokinetics were to be studied in all patients.Results: Eighty-one patients were assessable for toxicity, Patients with bilirubin levels greater than 1.5 mg/dL had substantial toxicity at all doses explored, whereas the toxicity for patients with elevated AST levels occurred at doses that ranged from 50 to 175 mg/m(2) administered over 24 hours. In most patients, the DLT was myelosuppression. The pharmacokinetic data were insufficient to adequately evaluate the relationship between pharmacokinetics and toxicity in patients who received 24-hour infusions but provided evidence of a longer exposure to paclitaxel than anticipated for the doses used in this study in the 3-hour infusion group.Conclusion: If paclitaxel is used for patients with elevated levels of AST or bilirubin, dose reductions are necessary, and an increase in toxicity can be anticipated. The increased myelosuppression observed is at least partially because of altered paclitaxel pharmacokinetics in such patients. (C) 1998 by American Society of Clinical Oncology.