Phase I and pharmacokinetic study of an oral platinum complex given daily for 5 days in patients with cancer
Phase I and pharmacokinetic study of an oral platinum complex given daily for 5 days in patients with cancer
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DOI：
10.1200/jco.1997.15.7.2691
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发表时间：
1997-07-01
影响因子：
45.3
通讯作者：
Judson, IR
中科院分区：
文献类型：
--
作者：
McKeage, MJ;Raynaud, F;Judson, IR
目的：我们的目的是确定最大耐受剂量（MTD）的临床毒性，药代动力学和药效学的口服JM 216给予每天一次，为期5天的癌症patients.Patients和方法患者符合标准的I期试验标准。口服JM 216，剂量基于患者体表面积，空腹，每日一次，连续5天，10、50和200 mg硬明胶胶囊，并口服止吐药。结果：32例患者口服JM 216 94个疗程，剂量范围为30 ~ 140 mg/m2体表面积，连续5 d。MTD为140 mg/m2/d，剂量限制性毒性为血小板减少和中性粒细胞减少。血液毒性是可逆的（最低值，17 - 21天;恢复期，28天），非累积性，并取决于剂量和既往治疗史。有2例血小板减少性败血症。三分之二的患者出现轻度恶心、呕吐或腹泻。无耳毒性、神经毒性、肾毒性或客观肿瘤缓解。JM 216剂量与第1天和第5天血浆超滤液浓度-时间曲线下面积（AUC; r = 0.78）之间存在显著相关性，表明药代动力学呈线性。有相当大的受试者间的药代动力学和药效学的变异性，但血浆超滤液AUC和血小板减少症的严重程度（R-2 = 0.83）之间的显着S形关系。结论：我们建议JM 216剂量为100和120 mg/m2/d × 5，分别为先前治疗和未治疗的患者，为II期试验。(C)1997年，美国临床肿瘤学会。
Purpose: We aimed to determine the maximum-tolerated dose (MTD) clinical toxicities, pharmacokinetics, and pharmacodynamics of oral JM216 given once daily for 5 days to cancer patients.Patients and Methods Patients who fulfilled standard phase I trial criteria were enrolled. Oral JM216 was given at doses based on patient body-surface area, on an empty stomach, once daily for 5 consecutive days, as 10-, 50-, and 200-mg hard gelatin capsules and with oral antiemetics. The pharmacokinetics of platinum were studied on days 1 and 5 of the first treatment course using atomic absorption spectrophotometry (AAS).Results: Thirty-two patients received 94 courses of oral JM216 at doses that ranged from 30 to 140 mg/m(2) body-surface area for 5 consecutive days. The MTD was 140 mg/m(2)/d, The dose-limiting toxicities were thrombocytopenia and neutropenia. Hematotoxicity was reversible (nadir, 17 to 21 days; recovery, 28 days), non-cumulative, and dependent on the dose and history of previous therapy. There were two instances of neutropenic sepsis. Two-thirds of patients experienced mild nausea, vomiting, or diarrhea. There was no ototoxicity, neurotoxicity, nephrotoxicity, or objective tumor responses. There was ct significant correlation between JM216 dose and the day 1 and 5 plasma ultrafiltrate area under the concentration-time curve (AUG; r = .78), which indicates linear pharmacokinetics. There was considerable intersubject pharmacokinetic and pharmacodynamic variability, but a significant sigmoidal relationship between the plasma ultrafiltrate AUC and severity of thrombocytopenia (R-2 = .83).Conclusion: We recommend JM216 doses of 100 and 120 mg/m(2)/d x 5 for previously treated and untreated patients, respectively, for phase II trials. (C) 1997 by American Society of Clinical Oncology.