Population pharmacokinetic model of ABL001/CTX-009 (anti-VEGF/DLL4) in adult cancer patients with solid tumor.

IF 5.7 2区 医学 Q1 Medicine Cancer Science Pub Date : 2024-10-07 DOI:10.1111/cas.16363
Joo Young Na, Juyeun Jeon, Ki Young Huh, Kyung-Sang Yu, Sangmi Lee, Jaehyun Eom, Jinhyung Ahn, Weon-Kyoo You, Jaeseong Oh
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Abstract

ABL001/CTX-009 is a bispecific antibody targeting delta-like ligand-4 and vascular endothelial growth factor A. In this study, we developed a population pharmacokinetic (PK) model of ABL001/CTX-009 in patients with solid tumors. A total of 712 plasma concentrations from 30 patients with relapsed or refractory solid tumors were collected from a phase 1 study (NCT03292783). A population PK model was developed using a nonlinear mixed-effect method and was evaluated by graphical and numerical methods. Using the model, the steady-state concentrations were simulated to compare weight-based and fixed-dose regimens and to find optimal dosing intervals. The PK of ABL001/CTX-009 was well described by a two-compartment model with a parallel first-order and Michaelis-Menten elimination kinetics. Body weight was selected as a significant covariate on V1. Model evaluation results suggested that the model was adequate and robust with good precision. Simulations after administrations of fixed or weight-based doses showed similar plasma concentrations. Additionally, 10 mg/kg for every other week and 15 mg/kg for every three-week administration showed comparable plasma concentrations. In conclusion, the model well described the plasma concentrations of ABL001/CTX-009 in patients with solid tumors. The simulation suggested that weight-based dose and fixed dose can provide equivalent systemic exposure.

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ABL001/CTX-009(抗血管内皮生长因子/DLL4)在成年实体瘤癌症患者中的群体药代动力学模型。
ABL001/CTX-009是一种靶向δ样配体-4和血管内皮生长因子A的双特异性抗体。在这项研究中,我们建立了ABL001/CTX-009在实体瘤患者中的群体药代动力学(PK)模型。我们从一项1期研究(NCT03292783)中收集了30名复发或难治性实体瘤患者的712个血浆浓度。研究人员采用非线性混合效应法建立了一个群体 PK 模型,并通过图形和数值方法对该模型进行了评估。利用该模型模拟了稳态浓度,以比较基于体重和固定剂量的治疗方案,并找到最佳给药间隔。ABL001/CTX-009的PK用平行一阶和Michaelis-Menten消除动力学的两室模型进行了很好的描述。体重被选为V1的重要协变量。模型评估结果表明,该模型充分、稳健、精确度高。在服用固定剂量或基于体重的剂量后进行的模拟显示出相似的血浆浓度。此外,每隔一周给药 10 毫克/千克和每三周给药 15 毫克/千克也显示出相似的血浆浓度。总之,该模型很好地描述了ABL001/CTX-009在实体瘤患者体内的血浆浓度。模拟结果表明,基于体重的剂量和固定剂量可提供等效的全身暴露。
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来源期刊
Cancer Science
Cancer Science ONCOLOGY-
CiteScore
9.90
自引率
3.50%
发文量
406
审稿时长
17 weeks
期刊介绍: Cancer Science (formerly Japanese Journal of Cancer Research) is a monthly publication of the Japanese Cancer Association. First published in 1907, the Journal continues to publish original articles, editorials, and letters to the editor, describing original research in the fields of basic, translational and clinical cancer research. The Journal also accepts reports and case reports. Cancer Science aims to present highly significant and timely findings that have a significant clinical impact on oncologists or that may alter the disease concept of a tumor. The Journal will not publish case reports that describe a rare tumor or condition without new findings to be added to previous reports; combination of different tumors without new suggestive findings for oncological research; remarkable effect of already known treatments without suggestive data to explain the exceptional result. Review articles may also be published.
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