Preliminary studies of a novel oral fluoropyrimidine carbamate: Capecitabine
Preliminary studies of a novel oral fluoropyrimidine carbamate: Capecitabine
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DOI：
10.1200/jco.1998.16.5.1795
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发表时间：
1998-05-01
影响因子：
45.3
通讯作者：
Griffin, T
中科院分区：
文献类型：
--
作者：
Budman, DR;Meropol, NJ;Griffin, T
目的：评价一种口服活性氟嘧啶的毒理学和药理学，将其分为两组，每日连续给药6周，并测定其每日最大耐受量(MTD)和建议的第二阶段每日剂量。患者和方法：选择器官功能正常、已接受治疗且知情同意的实体瘤患者，卡培他滨早晚两次口服，给至少3名患者服用ct，剂量为110 mg/m(2)，并通过改进的斐波那契方案逐步增加到1,657 mg/m(2)/d。在第1天和第15天采集药理样本，在前43天大约每3天进行一次毒性评估。治疗第42天评价抗肿瘤效果。结果：33例患者进入研究。1,331 mg/m(2)/d或以下几乎没有副作用，MTD为1,657 mg/m(2)/d，毒性有限，主要表现为掌底红肿、恶心、呕吐、眩晕、腹痛、腹泻和血小板减少。所有毒性反应都是可逆的。1例乳腺癌患者出现混合反应，药理学研究表明，母药在摄入后1小时迅速和广泛地代谢成细胞毒性代谢物，最大血药浓度(C-max)。浓度-时间曲线下面积(AUC)和C-max与给药剂量呈线性增加。结论：连续给药42天的II期给药剂量为1331 mg/m(2)/d，母体化合物和代谢物的药理参数呈线性关系。(C)1998年由美国临床肿瘤学会主办。
Purpose: To evaluate the toxicology and pharmacology of an orally active fluoropyrimidine given as a continuous daily dose divided into two portions for 6 weeks, and to determine the maximal-tolerated daily dose (MTD) and the suggested phase II daily dose.Patients and Methods: Solid-tumor patients with a Karnofsky performance status greater than 70 who had normal organ function and resolution of the effects of prior therapy, and who gave informed written consent, were enrolled, Oral capecitabine, as a divided morning and evening dose, was administered to cohorts of ct minimum of 3 patients starling at 110 mg/m(2) and escalating by means of a modified Fibonacci scheme to 1,657 mg/m(2)/d. Pharmacologic samples were obtained on days 1 and 15, Toxicity evaluations were performed approximately every 3 days for the first 43 days. Antitumor effect was evaluated at day 42 of therapy.Results: Thirty-three patients entered the study. Few side effects occurred at or below 1,331 mg/m(2)/d. The MTD was 1,657 mg/m(2)/d with limiting toxicities of palmar-plantar erythrodysesthesia, nausea, vomiting, vertigo, abdominal pain, diarrhea, and thrombocytopenia. All toxicities were reversible. A mixed response was seen in one breast cancer patient, Pharmacologic studies showed rapid and extensive metabolism of the parent drug into cytotoxic metabolites with a maximum plasma concentration (C-max) 1 hour after ingestion. Linear increases in the area under the concentmtion-time curve (AUC) and C-max were seen with linear increases in administered dose.Conclusion: The suggested phase II dose on a continuous 42-day dosing schedule is 1,331 mg/m(2)/d. Linear pharmacologic parameters of the parent compound and metabolites are demonstrated. (C) 1998 by American Society of Clinical Oncology.