Phase I and pharmacokinetic study of temozolomide on a daily-for-5-days schedule in patients with advanced solid malignancies
Phase I and pharmacokinetic study of temozolomide on a daily-for-5-days schedule in patients with advanced solid malignancies
复制标题
DOI：
10.1200/jco.1999.17.8.2604
复制
发表时间：
1999-08-01
影响因子：
45.3
通讯作者：
Rowinsky, EK
中科院分区：
文献类型：
--
作者：
Hammond, LA;Eckardt, JR;Rowinsky, EK
目的：为了确定的主要毒性，表征替莫唑胺（TMZ）的药代动力学（PK）和药效学（PD）的每日5天的时间表，并建议剂量为随后的疾病导向的研究在最低限度的预处理（MP）和重度预处理（HP）patients.Patients和方法：患者接受TMZ作为一个单一的口服剂量，每天连续5天，每28天。在MP和HP患者的不同队列中，TMZ剂量从100 mg/m2/d递增至150 mg/m2/d，从150 mg/m2/d递增至200 mg/m2/d。在第1天和第5天采集PK血浆样本。结果：24例患者共接受TMZ治疗85个疗程。血小板减少症和中性粒细胞减少症是TMZ在该方案中的主要剂量限制性毒性（DLT）。在MP和HP患者中，TMZ剂量超过150 mg/m2/d时，重度骨髓抑制效应的累积发生率高得不可接受。TMZ吸收迅速，平均在0.90小时内达到最大浓度，消除迅速，半衰期和全身清除率（Cl-S/F）平均分别为1.8小时和115 mL/min/m2。当清除率标准化为体表面积（BSA）时，CIS/F的患者间变异性在第1天从20%降至13%，在第5天从16%降至10%。发生DLT的患者在第5天的最大药物浓度（中位数16 v9.5 μ g/mL，P = 0.0084）和浓度-时间曲线下面积（中位数36 v23 μ g·h/ml，P = 0.0019）值显著更高。结论：既往骨髓抑制治疗不是毒性的决定因素。MP和HP患者对TMZ 150 mg/m2/d每日单次口服给药，持续5天，每4周一次的耐受性良好，较高剂量导致不可接受的高重度血液学毒性发生率。TMZ剂量应根据BSA个体化，而不是对所有个体使用预先指定的口服剂量。TMZ是与其他细胞毒性、生物学和靶向治疗药物联合开发用于相关恶性肿瘤患者的最佳药物。(C)1999年，美国临床肿瘤学会。
Purpose: To determine the principal toxicities, characterize the pharmacokinetics (PKs) and pharmacodynamics (PDs) of temozolomide (TMZ) on a daily-for-5-days schedule, and recommend a dose for subsequent disease-directed studies in both minimally pretreated (MP) and heavily pretreated (HP) patients.Patients and Methods: patients received TMZ as a single oral dose daily for 5 consecutive days every 28 days. TMZ doses were escalated from 100 to 150, and 150 to 200 mg/m(2)/d in separate cohorts of MP and HP patients. PK plasma was sampled on days 1 and 5. TMZ concentrations were analyzed and pertinent PK parameters were related to the principal toxicities of TMZ in PD analyses.Results: Twenty-four patients were treated with 85 courses of TMZ. Thrombocytopenia and neutropenia were the principal dose-limiting toxicities (DLTs) of TMZ on this schedule. The cumulative rate of severe myelosuppressive effects was unacceptably high at TMZ doses exceeding 150 mg/m2/d in both MP and HP patients. TMZ was absorbed rapidly with maximum concentrations achieved in 0.90 hours, on average, and elimination was rapid, with a half-life and systemic clearance rate (Cl-S/F) averaging 1.8 hours and 115 mL/min/m(2), respectively. When clearance was normalized to body-surface area (BSA), interpatient variability in CIS/F was reduced from 20% to 13% on day 1 and from 16% to 10% on day 5. patients who experienced DLT had significantly higher maximum drug concentration (median 16 v 9.5 mu g/mL, P = .0084) and area under the concentration-time curve (median 36 v 23 mu g-h/ml, P = .0019) values on day 5.Conclusion: Prior myelosuppressive therapy war not a determinant of toxicity. TMZ 150 mg/m2/d administered as a single oral dose daily for 5 days every 4 weeks is well tolerated by MP and HP patients, with higher doses resulting in unacceptably high rates of severe hematologic toxicity. TMZ doses should be individualized according to BSA rather than use of a prespecified oral dose for all individuals. TMZ is an optimal agent to develop in combination with other cytotoxic, biologic, and targeted therapeutics for patients with relevant malignancies. (C) 1999 by American Society of Clinical Oncology.