Administration of CI-1033, an irreversible Pan-erbB tyrosine kinase inhibitor, is feasible on a 7-day on, 7-day off schedule: A phase I pharmacokinetic and food effect study
Administration of CI-1033, an irreversible Pan-erbB tyrosine kinase inhibitor, is feasible on a 7-day on, 7-day off schedule: A phase I pharmacokinetic and food effect study
复制标题
DOI：
10.1158/1078-0432.ccr-04-1187
复制
发表时间：
2004-11-01
影响因子：
11.5
通讯作者：
Rowinsky, EK
中科院分区：
文献类型：
--
作者：
Calvo, E;Tolcher, AW;Rowinsky, EK
目的：确定间歇给药CI-1033（一种口服4-苯胺基喹唑啉，其不可逆地抑制所有erbB亚家族的酪氨酸激酶结构域）的最大耐受剂量，并评估CI-1033与食物的相互作用对药代动力学行为的影响。向患有晚期实体恶性肿瘤的患者施用递增剂量的CI-1033，从300 mg/天的剂量水平每隔一周持续7天。使用所有可评价患者的血浆浓度-时间数据集开发群体药代动力学模型。非房室方法被用来独立评估CI-1033的吸收和bioavailability.Results的高脂餐的效果：24例患者治疗69二十八天的课程。在300 mg/天剂量水平下观察到不可接受毒性的发生率，主要是腹泻和皮疹。在250 mg/天水平下，毒性是可控的，延长给药是可行的。具有一级吸收和消除的一室线性模型充分描述了药代动力学分布。CL/F、表观分布容积（V-d/F）和k（a）（平均值+/-相对SD）分别为280 L/h +/-33%、684 L +/-20%和0.35 h（-1）+/-69%。在2至4小时内达到C-max值。全身CI-1033暴露量在很大程度上不受高脂肪餐给药的影响。在临床前试验中，250 mg浓度值超过延长pan-erbB酪氨酸激酶抑制所需的IC 50值。结论：该方案的推荐剂量为250 mg/天。其耐受性和在最大耐受剂量下达到的浓度的生物学相关性需要考虑疾病导向评价。这种间歇性治疗方案可以在不考虑膳食的情况下使用。
Purpose: To determine the maximum tolerated dose of administrating CI-1033, an oral 4-anilinoquinazoline that irreversibly inhibits the tyrosine kinase domain of all erbB subfamilies, on an intermittent schedule, and assess the interaction of CI-1033 with food on the pharmaco fkinetic behavior.Experimental Design: Escalating doses of CI-1033 from a dose level of 300 mg/day for 7 days every other week were administered to patients with advanced solid malignancies. Plasma concentration-time data sets from all evaluable patients were used to develop a population pharmacokinetic model. Noncompartmental methods were used to independently assess the effect of a high-fat meal on CI-1033 absorption and bioavailability.Results: Twenty-four patients were treated with 69 twenty-eight day courses. The incidence of unacceptable toxicity, principally diarrhea and skin rash, was observed at the 300 mg/day dose level. At the 250 mg/day level, toxicity was manageable, and protracted administration was feasible. A one-compartment linear model with first-order absorption and elimination adequately described the pharmacokinetic disposition. CL/F, apparent volume of distribution (V-d/F), and k(a) (mean +/- relative SD) were 280 L/hour +/- 33%, 684 L +/- 20%, and 0.35 hour(-1) +/- 69%, respectively. C-max values were achieved in 2 to 4 hours. Systemic CI-1033 exposure was largely unaffected by administration of a high-fat meal. At 250 mg, concentration values exceeded IC50 values required for prolonged pan-erbB tyrosine kinase inhibition in preclinical assays. Conclusions: The recommended dose on this schedule is 250 mg/day. Its tolerability and the biological relevance of concentrations achieved at the maximal tolerated dose warrant consideration of disease-directed evaluations. This intermittent treatment schedule can be used without regard to meals.