Clovis Oncology, Inc., 5500 Flatiron Pkwy, Boulder, CO, 80301, USA.
Nuventra LLC, Durham, NC, USA.
Eur J Drug Metab Pharmacokinet. 2022 Sep;47(5):711-723. doi: 10.1007/s13318-022-00773-w. Epub 2022 Jul 18.
Lucitanib is an oral, potent, selective inhibitor of the tyrosine kinase activity of vascular endothelial growth factor receptors 1‒3, fibroblast growth factor receptors 1‒3, and platelet-derived growth factor receptors alpha/beta.
We aimed to develop a population pharmacokinetics (PopPK) model for lucitanib in patients with advanced cancers.
PopPK analyses were based on intensive and sparse oral pharmacokinetic data from 5 phase 1/2 clinical studies of lucitanib in a total of 403 patients with advanced cancers. Lucitanib was administered at 5‒30 mg daily doses as 1 of 2 immediate-release oral formulations: a film-coated tablet or a hard gelatin capsule.
Lucitanib pharmacokinetics were best described by a 2-compartment model with zero-order release into the dosing compartment, followed by first-order absorption and first-order elimination. Large between-subject pharmacokinetic variability was partially explained by body weight. No effects of demographics or tumor type on lucitanib pharmacokinetics were observed. The model suggested that the formulation impacted release duration (tablet, 0.243 h; capsule, 0.814 h), but the effect was not considered clinically meaningful. No statistically significant effects were detected for concomitant cytochrome P450 (CYP) 3A4 inhibitors or inducers, CYP2C8 or P-glycoprotein inhibitors, serum albumin, mild/moderate renal impairment, or mild hepatic impairment. Concomitant proton pump inhibitors had no clinically significant effect on lucitanib absorption.
The PopPK model adequately described lucitanib pharmacokinetics. High between-subject pharmacokinetic variability supports a safety-based dose-titration strategy currently being used in an ongoing clinical study of lucitanib to optimize drug exposure and clinical benefit.
ClinicalTrials.gov Identifier: NCT01283945, NCT02053636, ISRCTN23201971, NCT02202746, NCT02109016.
Lucitanib 是一种口服、强效、选择性的血管内皮生长因子受体 1-3、成纤维细胞生长因子受体 1-3 和血小板衍生生长因子受体α/β酪氨酸激酶抑制剂。
我们旨在建立晚期癌症患者 lucitanib 的群体药代动力学（PopPK）模型。
PopPK 分析基于 5 项 lucitanib Ⅰ/Ⅱ期临床研究中 403 例晚期癌症患者的密集和稀疏口服药代动力学数据。Lucitanib 以 5-30mg 每日剂量作为 2 种速释口服制剂之一给药：薄膜包衣片或硬胶囊。
Lucitanib 药代动力学最好用 2 室模型描述，零级释放到给药室，随后是一级吸收和一级消除。较大的个体间药代动力学变异性部分由体重解释。未观察到人口统计学或肿瘤类型对 lucitanib 药代动力学的影响。该模型表明制剂影响释放持续时间（片剂，0.243h；胶囊，0.814h），但影响无临床意义。未检测到伴随细胞色素 P450（CYP）3A4 抑制剂或诱导剂、CYP2C8 或 P-糖蛋白抑制剂、血清白蛋白、轻度/中度肾功能损害或轻度肝损害对 lucitanib 药代动力学的统计学显著影响。伴随质子泵抑制剂对 lucitanib 吸收无临床显著影响。
PopPK 模型充分描述了 lucitanib 药代动力学。高个体间药代动力学变异性支持目前正在进行的 lucitanib 临床研究中基于安全性的剂量滴定策略，以优化药物暴露和临床获益。
ClinicalTrials.gov 标识符：NCT01283945、NCT02053636、ISRCTN23201971、NCT02202746、NCT02109016。
