实体瘤患者中cobimetinib的群体药代动力学和给药意义。

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Han K, Jin JY, Marchand M, Eppler S, Choong N, Hack SP, Tikoo N, Bruno R, Dresser M, Musib L, Budha NR

实体瘤患者中cobimetinib的群体药代动力学和给药意义。

《肿瘤化疗药物》2015年11月;76(5):917-24。doi: 10.1007 / s00280 - 015 - 2862 - 0。Epub 2015 9月13日。

PubMed ID

26365290 (PubMed视图

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摘要

目的:研究cobimetinib药代动力学特征，评估临床相关协变量对cobimetinib药代动力学的影响。方法:从3项临床研究(MEK4592g, NO25395, GO28141)中487例各种实体瘤(主要是黑色素瘤)患者中收集血浆样本(N = 4886)。Cobimetinib口服，每日一次，以单药或与vemurafenib联合用药为28天给药周期，分别为21天开/7天停、14天开/14天停或28天开。Cobimetinib的剂量从2.1到125毫克不等。使用NONMEM进行药代动力学分析。结果:具有一级吸收、滞后时间和一级消除的线性双室模型描述了cobimetinib的药代动力学。表观清除率(CL/F)、中心分布容积(V2/F)和终末半衰期的典型估计(个体间变异)分别为322 L/天(58%)、511 L(49%)和2.2天。相对生物利用度的场合间变异估计为46%。CL/F随年龄增长而降低。V2/F随体重(BWT)增加而增加。 However, the impact of age and BWT on cobimetinib steady-state exposure (peak and trough concentrations and AUC following the recommended daily dose of 60 mg 21-day-on/7-day-off) was limited (<25 % changes across the distribution of age and BWT). No significant difference in cobimetinib pharmacokinetics or steady-state exposure was observed between patient subgroups based on sex, renal function, ECOG score, hepatic function tests, race, region, cancer type, and co-administration of moderate and weak CYP3A inducers or inhibitors and vemurafenib. CONCLUSION: A population pharmacokinetic model was developed for cobimetinib in cancer patients. Covariates had minimal impact on steady-state exposure, suggesting no need for dose adjustments and supporting the recommended dose for all patients.

引用本文的药物库数据

药物

Cobimetinib