Piscitelli Joseph, Hahn Erik, Wollenberg Lance, Chavira Renae, Del Frari Laurence, Reddy Micaela B
Pfizer Inc, San Diego, CA, 92121, USA.
Pfizer Inc, Boulder, CO, USA.
Clin Pharmacokinet. 2025 Aug;64(8):1217-1230. doi: 10.1007/s40262-025-01509-0. Epub 2025 Jun 23.
Binimetinib is approved for multiple indications at a therapeutic dose of 45 mg twice a day (BID), in combination with encorafenib. A clinical hepatic impairment (HI) study was designed to evaluate the pharmacokinetics (PK), safety, and tolerability of a single oral dose of binimetinib in participants with mild, moderate, and severe HI compared with demographically matched healthy participants with respect to age, gender, and body weight.
Participants were enrolled according to National Cancer Institute (NCI) classification criteria for hepatic function based on their total bilirubin and aspartate aminotransferase levels at screening. Participants enrolled into Group 1 (normal hepatic function) were matched to participants enrolled into Groups 2, 3, and 4 (mild, moderate, and severe HI, respectively) with respect to age, gender, and body weight. Dose-normalized PK parameters were evaluated because of a difference in doses for the severe HI group compared to the other groups, with the dose reduction due to the increased exposures observed in the moderate HI group.
Among 27 PK evaluable participants, changes in binimetinib dose-normalized PK parameters C/D and AUC/D were minimal in participants with mild HI compared to the normal hepatic function group. Both the moderate and severe HI groups had significant changes as AUC/D increased by 81% and 111%, respectively, compared to the normal hepatic function group. Unbound AUC/D for the moderate and severe HI groups increased by 280% and 248% compared to the normal hepatic function group, respectively.
Based on these findings on total and unbound exposures, dose reductions are recommended for binimetinib in cancer patients with moderate and severe HI.
ClinicalTrials.gov NCT02050815, registered 29 January 2014.
比美替尼以每日两次、每次45毫克（bid）的治疗剂量获批用于多种适应症，与恩考芬尼联合使用。一项临床肝损伤（HI）研究旨在评估单剂量口服比美替尼在轻度、中度和重度HI患者中的药代动力学（PK）、安全性和耐受性，并与年龄、性别和体重相匹配的健康参与者进行比较。
根据美国国立癌症研究所（NCI）基于筛查时总胆红素和天冬氨酸转氨酶水平的肝功能分类标准招募参与者。将第1组（肝功能正常）的参与者与第2、3和4组（分别为轻度、中度和重度HI）的参与者在年龄、性别和体重方面进行匹配。由于重度HI组与其他组的剂量不同，因此评估了剂量标准化的PK参数，中度HI组因观察到暴露增加而降低了剂量。
在27名可评估PK的参与者中，与肝功能正常组相比，轻度HI参与者的比美替尼剂量标准化PK参数C/D和AUC/D变化最小。中度和重度HI组均有显著变化，与肝功能正常组相比，AUC/D分别增加了81%和111%。与肝功能正常组相比，中度和重度HI组的未结合AUC/D分别增加了280%和248%。
基于这些关于总暴露量和未结合暴露量的研究结果，建议对中度和重度HI的癌症患者减少比美替尼的剂量。
ClinicalTrials.gov NCT02050815，于2014年1月29日注册。
