Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, PO Box 9600 NL, 2300 RC, Leiden, The Netherlands,
Cancer Chemother Pharmacol. 2014 Feb;73(2):429-33. doi: 10.1007/s00280-013-2353-0. Epub 2013 Nov 21.
Panitumumab is used for the treatment for metastatic RAS wild-type colorectal cancer (mCRC). It is likely that many of these patients will present with liver metastases and some with liver dysfunction. The pharmacokinetics in patients with hepatic impairment has not been investigated, and dosage adjustments are undetermined. Here, we present a case of a patient with progressive mCRC and liver dysfunction.
A heavily pretreated KRAS wild-type mCRC patient with liver disease Child-Pugh class B was treated with 2-weekly intravenous panitumumab (6 mg/kg). The patient received 2 doses of 490 mg i.v. panitumumab after which progressive disease was documented. Toxicities were graded using CTCAEv4.0. Serum samples were collected, and panitumumab concentrations were determined using a validated immunoassay. Pharmacokinetic parameters after the first dose, including dose-normalized AUC from time zero-day 14, clearance (CL), and elimination half-life (T1/2), were estimated via trapezoidal noncompartmental methods. Data were compared to historical data from a population with adequate liver function, as reported by Stephenson (Clin Colorectal Cancer, 8:29-37, 2009). Values within the range of the mean ±1 standard deviation (SD) were considered not deviant.
Calculated AUC after the first dose of 6 mg/kg panitumumab in this patient with hepatic dysfunction was 877 μg day/mL (Stephenson's cohort 1: 744 ± 195 μg day/mL). Estimated T1/2 was 3.58 days (5.28 ± 1.90 days), and CL was 6.9 mL/day/kg (8.21 ± 3.79 mL/day/kg). Estimated PK parameters during the first cycle were inside reported mean ±1 SD of historical controls without liver dysfunction. No toxicity was reported during treatment; particularly, no diarrhea and skin toxicity were noticed.
The pharmacokinetics of panitumumab in this patient suffering from metastatic colorectal cancer with liver dysfunction Child-Pugh class B was similar compared to patients with adequate liver function. Moreover, no substantial toxicity was detected. The here-presented data may help clinical decision making in real-life practice. Two-weekly panitumumab monotherapy seems to be safely applicable in patients with KRAS wild-type mCRC and hepatic dysfunction, without the need for any dose adjustments.
帕尼单抗用于治疗转移性 RAS 野生型结直肠癌（mCRC）。这些患者中许多人可能会出现肝转移，有些人会出现肝功能障碍。尚未研究肝功能损害患者的药代动力学，也未确定剂量调整。在此，我们报告了一例进展性 mCRC 伴肝功能障碍的患者。
一位经大量预处理的 KRAS 野生型 mCRC 伴肝病 Child-Pugh 分级 B 的患者接受每周两次静脉注射帕尼单抗（6mg/kg）治疗。患者接受了两剂 490mg 的静脉注射帕尼单抗后，发现疾病进展。使用 CTCAEv4.0 对毒性进行分级。收集血清样本，并使用经过验证的免疫分析法测定帕尼单抗浓度。通过梯形非房室法估算首次剂量后的药代动力学参数，包括从第 0 天到第 14 天的时间零剂量归一化 AUC、清除率（CL）和消除半衰期（T1/2）。数据与 Stephenson（Clin Colorectal Cancer，8：29-37，2009）报告的具有足够肝功能的人群的历史数据进行比较。在均值±1 标准差（SD）范围内的值被认为没有偏差。
该患者肝功能障碍时首次给予 6mg/kg 帕尼单抗后的 AUC 计算值为 877μg·day/mL（Stephenson 队列 1：744±195μg·day/mL）。估计 T1/2 为 3.58 天（5.28±1.90 天），CL 为 6.9mL/天/kg（8.21±3.79mL/天/kg）。第一个周期的估计 PK 参数在无肝功能障碍的历史对照的报告均值±1 SD 范围内。治疗期间未报告毒性；特别是，未注意到腹泻和皮肤毒性。
患有肝功能障碍 Child-Pugh 分级 B 的转移性结直肠癌患者的帕尼单抗药代动力学与肝功能正常的患者相似。此外，未检测到实质性毒性。本研究结果可能有助于临床实践中的决策。两周一次的帕尼单抗单药治疗似乎可安全应用于 KRAS 野生型 mCRC 伴肝功能障碍的患者，无需调整剂量。
