Rudek Michelle A, Donehower Ross C, Statkevich Paul, Batra Vijay K, Cutler David L, Baker Sharyn D
Division of Medical Oncology, The Sidney Kimmel Comprehensive Cancer Center, John Hopkins University, Baltimore, Maryland 21231, USA.
Pharmacotherapy. 2004 Jan;24(1):16-25. doi: 10.1592/phco.24.1.16.34800.
To determine the maximum tolerated dose, dose-limiting toxicity, pharmacokinetics, and potential antitumor activity of temozolomide administered as a single dose every 28 days.
Open label, phase I, dose-escalation trial.
University-affiliated cancer center.
Eleven patients aged 33-73 years with a documented solid tumor or lymphoma who failed therapy of proven efficacy for their disease or had a disease for which no conventional therapy was available.
Temozolomide 500 mg/m2 was administered as a single oral dose every 28 days. Doses were escalated to 750 or 1000 mg/m2. No intrapatient dose escalation was allowed. At least two patients were enrolled at each dose level. Patients who did not have progressive disease and did not experience a dose-limiting toxicity, or experienced a dose-limiting toxicity but were eligible for dose reduction, were eligible to continue on the study.
Pharmacokinetic analysis was performed for temozolomide and its active metabolite, 5-(3-methyltriazeno)-imidazole-4-carboxamide (MTIC). Neutropenia and thrombocytopenia were dose limiting at 1000 mg/m2. Temozolomide was absorbed rapidly (mean time to maximum concentration 1.4 hrs) and eliminated, with average half-life and apparent oral systemic clearance values of 1.8 hours and 97 ml/minute/m2, respectively. Mean systemic exposure to MTIC was 3.7% of temozolomide. No objective responses were observed. The maximum tolerated dose of temozolomide was 750 mg/m2.
Temozolomide 750 mg/m2 administered orally every 28 days was well tolerated. Alternate temozolomide dosing schedules such as continuous daily administration may enhance antitumor activity through sustained depletion of the DNA repair protein O6-alkylguanine DNA alkyltransferase.
确定每28天单次给药的替莫唑胺的最大耐受剂量、剂量限制性毒性、药代动力学及潜在抗肿瘤活性。
开放标签的I期剂量递增试验。
大学附属医院癌症中心。
11例年龄在33 - 73岁之间的患者，患有确诊的实体瘤或淋巴瘤，其疾病治疗失败或所患疾病无可用的传统治疗方法。
替莫唑胺500mg/m²每28天口服单次给药。剂量递增至750或1000mg/m²。不允许患者内剂量递增。每个剂量水平至少入组2例患者。未出现疾病进展且未发生剂量限制性毒性，或发生剂量限制性毒性但符合剂量降低条件的患者，有资格继续参与研究。
对替莫唑胺及其活性代谢产物5-(3-甲基三氮烯)-咪唑-4-甲酰胺（MTIC）进行药代动力学分析。1000mg/m²时中性粒细胞减少和血小板减少为剂量限制性毒性。替莫唑胺吸收迅速（平均达峰时间1.4小时）并被清除，平均半衰期和表观口服全身清除率分别为1.8小时和97ml/分钟/m²。MTIC的平均全身暴露量为替莫唑胺的3.7%。未观察到客观缓解。替莫唑胺的最大耐受剂量为750mg/m²。
每28天口服750mg/m²的替莫唑胺耐受性良好。替莫唑胺的其他给药方案，如持续每日给药，可能通过持续消耗DNA修复蛋白O6-烷基鸟嘌呤-DNA烷基转移酶来增强抗肿瘤活性。
