Miller Antonius A, Murry Daryl J, Owzar Kouros, Hollis Donna R, Lewis Lionel D, Kindler Hedy L, Marshall John L, Villalona-Calero Miguel A, Edelman Martin J, Hohl Raymond J, Lichtman Stuart M, Ratain Mark J
Wake Forest University School of Medicine, Winston-Salem, NC 27157-1082, USA.
J Clin Oncol. 2007 Jul 20;25(21):3055-60. doi: 10.1200/JCO.2007.11.6210.
We investigated dose and pharmacokinetics of erlotinib in patients with hepatic dysfunction or renal dysfunction.
Patients were assigned to one of three cohorts: cohort 1, AST > or = 3x upper limit of normal; cohort 2, direct bilirubin of 1 to 7 mg/dL; and cohort 3, creatinine of 1.6 to 5.0 mg/dL. Cohort 1a was amended for albumin less than 2.5 g/dL. Erlotinib was administered orally daily to groups of at least three assessable patients in escalating doses of 50, 75, 100, and 150 mg, starting with 50 mg in hepatic dysfunction patients and 75 mg in renal dysfunction patients.
Between December 2001 and May 2005, 55 patients were accrued. The distribution of assessable patients was: two of three in cohort 1, three of three in cohort 1a, 16 of 30 in cohort 2, and 18 of 18 in cohort 3. Dose-limiting toxicity (DLT) consisted of elevation of both total and direct bilirubin 1.5x baseline in three patients (cohort 1: one of five patients at 50 mg; cohort 2: two of six patients at 100 mg). In cohort 2, one of seven patients had DLT at 75 mg. No DLT was encountered in cohort 3 with 12 patients at 150 mg. Apparent oral clearance (mean +/- standard deviation) was cohort dependent as follows: 1.9 +/- 0.2 L/h in cohort 1; 3.7 +/- 4.7 L/h in cohort 1a; 2.4 +/- 1.1 L/h in cohort 2; and 4.5 +/- 2.7 L/h in cohort 3 (Kruskal-Wallis, P < .017).
Patients with renal dysfunction tolerate 150 mg of erlotinib daily and seem to have an erlotinib clearance similar to patients without organ dysfunction. Patients with hepatic dysfunction should be treated at a reduced dose (ie, 75 mg daily) consistent with their reduced clearance.
我们研究了厄洛替尼在肝功能不全或肾功能不全患者中的剂量及药代动力学情况。
患者被分为三个队列之一：队列1，谷草转氨酶（AST）>或=正常上限的3倍；队列2，直接胆红素为1至7mg/dL；队列3，肌酐为1.6至5.0mg/dL。队列1a针对白蛋白低于2.5g/dL进行了修正。厄洛替尼以50、75、100和150mg的递增剂量每日口服给药，每组至少有三名可评估患者，肝功能不全患者从50mg开始，肾功能不全患者从75mg开始。
在2001年12月至2005年5月期间，共纳入55例患者。可评估患者的分布情况如下：队列1中3例中的2例；队列1a中3例中的3例；队列2中30例中的16例；队列3中18例中的18例。剂量限制毒性（DLT）包括3例患者（队列1：50mg剂量组的5例患者中的1例；队列2：100mg剂量组的6例患者中的2例）总胆红素和直接胆红素均升高至基线的1.5倍。在队列2中，75mg剂量组的7例患者中有1例出现DLT。队列3中150mg剂量的12例患者未出现DLT。表观口服清除率（平均值±标准差）因队列而异，如下所示：队列1为1.9±0.2L/h；队列1a为3.7±4.7L/h；队列2为2.4±1.1L/h；队列3为4.5±2.7L/h（Kruskal-Wallis检验，P<.017）。
肾功能不全患者每日耐受150mg厄洛替尼，其厄洛替尼清除率似乎与无器官功能障碍的患者相似。肝功能不全患者应以降低剂量（即每日75mg）进行治疗，这与其清除率降低相一致。
