Miller Antonius A, Murry Daryl J, Owzar Kouros, Hollis Donna R, Kennedy Erin B, Abou-Alfa Ghassan, Desai Apurva, Hwang Jimmy, Villalona-Calero Miguel A, Dees E Claire, Lewis Lionel D, Fakih Marwan G, Edelman Martin J, Millard Fred, Frank Richard C, Hohl Raymond J, Ratain Mark J
Comprehensive Cancer Center of Wake Forest University, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
J Clin Oncol. 2009 Apr 10;27(11):1800-5. doi: 10.1200/JCO.2008.20.0931. Epub 2009 Mar 2.
We sought to characterize the pharmacokinetics (PK) and determine a tolerable dose of oral sorafenib in patients with hepatic or renal dysfunction.
Patients were assigned to one of nine cohorts: cohort 1, bilirubin < or = upper limit of normal (ULN) and AST < or = ULN and creatinine clearance (CC) > or = 60 mL/min; cohort 2, bilirubin more than ULN but < or = 1.5x ULN and/or AST more than ULN; cohort 3, CC between 40 and 59 mL/min; cohort 4, bilirubin more than 1.5x ULN to < or = 3x ULN (any AST); cohort 5, CC between 20 and 39 mL/min; cohort 6, bilirubin more than 3x ULN to 10x ULN (any AST); cohort 7, CC less than 20 mL/min; cohort 8, albumin less than 2.5 mg/dL (any bilirubin/AST); and cohort 9, hemodialysis. Sorafenib was administered as a 400-mg dose on day 1 for PK, and continuous daily dosing started on day 8.
Of 150 registered patients, 138 patients were treated. With the exception of cohorts 6 and 7, at least 12 patients per cohort were assessable, and the dose level with prospectively defined dose-limiting toxicity in less than one third of patients by day 29 was considered tolerable. No significant associations between the sorafenib PK and cohort were found.
We recommend the following empiric sorafenib starting doses by cohort: cohort 1, 400 mg twice a day; cohort 2, 400 mg twice a day; cohort 3, 400 mg twice a day; cohort 4, 200 mg twice a day; cohort 5, 200 mg twice a day; cohort 6, not even 200 mg every third day tolerable; cohort 7, not defined; cohort 8, 200 mg each day; and cohort 9, 200 mg each day.
我们试图描述肝或肾功能不全患者口服索拉非尼的药代动力学（PK）特征并确定其可耐受剂量。
患者被分配到九个队列之一：队列1，胆红素≤正常上限（ULN）且AST≤ULN且肌酐清除率（CC）≥60 mL/分钟；队列2，胆红素高于ULN但≤1.5倍ULN和/或AST高于ULN；队列3，CC在40至59 mL/分钟之间；队列4，胆红素高于1.5倍ULN至≤3倍ULN（任何AST）；队列5，CC在20至39 mL/分钟之间；队列6，胆红素高于3倍ULN至10倍ULN（任何AST）；队列7，CC低于20 mL/分钟；队列8，白蛋白低于2.5 mg/dL（任何胆红素/AST）；队列9，血液透析。第1天给予索拉非尼400 mg剂量用于PK研究，第8天开始每日持续给药。
150名登记患者中，138名患者接受了治疗。除队列6和7外，每个队列至少有12名患者可评估，且到第29天在前瞻性定义的剂量限制毒性患者中不到三分之一的剂量水平被认为是可耐受的。未发现索拉非尼PK与队列之间存在显著关联。
我们根据队列推荐以下经验性索拉非尼起始剂量：队列1，每日两次，每次400 mg；队列2，每日两次，每次400 mg；队列3，每日两次，每次400 mg；队列4，每日两次，每次200 mg；队列5，每日两次，每次200 mg；队列6，每三天甚至200 mg都不可耐受；队列7，未定义；队列8，每日200 mg；队列9，每日200 mg。
