图卡替尼在健康参与者和乳腺癌或结直肠癌患者中的群体药代动力学分析。

IF 4.6 2区 医学 Q1 PHARMACOLOGY & PHARMACY
Clinical Pharmacokinetics Pub Date : 2024-10-01 Epub Date: 2024-10-05 DOI:10.1007/s40262-024-01412-0
Daping Zhang, Adekemi Taylor, Jie Janet Zhao, Christopher J Endres, Ariel Topletz-Erickson
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引用次数: 0

摘要

背景和目的图卡替尼是一种高选择性、口服、可逆的人类表皮生长因子受体2(HER2)特异性酪氨酸激酶抑制剂。图卡替尼已获批与曲妥珠单抗和卡培他滨联用治疗晚期HER2阳性(HER2+)不可切除或转移性乳腺癌,以及与曲妥珠单抗联用治疗RAS野生型HER2+不可切除或转移性结直肠癌,成人剂量为300毫克,每天两次。本研究旨在描述健康志愿者和HER2+转移性乳腺癌或结直肠癌患者体内图卡替尼的药代动力学(PK)特征,并评估PK变异性的来源:采用非线性混合效应建模方法,根据四项健康参与者研究和三项HER2+转移性乳腺癌或转移性结直肠癌患者研究的数据,建立了群体药代动力学模型。对临床相关协变量进行了评估,以评估其对暴露的影响,并通过预测校正视觉预测检查对模型的整体性能进行了评估:结果:在151名健康参与者和132名患者中,具有线性消除和一阶吸收(前有滞后时间)的两室药动学模型充分描述了图卡替尼的药动学特征。与健康参试者相比,HER2+转移性结直肠癌和HER2+转移性乳腺癌患者的图卡替尼稳态暴露量(浓度-时间曲线下面积)分别增加了1.2倍和2.1倍。包括轻度肝肾功能损害在内的其他协变量均未对图卡替尼药代动力学产生影响:结论:已发现的具有统计学意义的协变量的影响不具有临床意义。临床试验注册:NCT03723395,NCT03723395,NCT03723395,NCT03723395,NCT03723395,NCT03723395,NCT03723395,NCT03723395:NCT03723395、NCT03914755、NCT03826602、NCT03043313、NCT01983501、NCT02025192。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Population Pharmacokinetic Analysis of Tucatinib in Healthy Participants and Patients with Breast Cancer or Colorectal Cancer.

Background and objective: Tucatinib is a highly selective, oral, reversible, human epidermal growth factor receptor 2 (HER2)-specific tyrosine kinase inhibitor. Tucatinib is approved at a 300-mg twice-daily dose in adults in combination with trastuzumab and capecitabine for advanced HER2-postitive (HER2+) unresectable or metastatic breast cancer and in combination with trastuzumab for RAS wild-type HER2+ unresectable or metastatic colorectal cancer. This study sought to characterize the pharmacokinetics (PK) and assess sources of PK variability of tucatinib in healthy volunteers and in patients with HER2+ metastatic breast or colorectal cancers.

Methods: A population pharmacokinetic model was developed based on data from four healthy participant studies and three studies in patients with either HER2+ metastatic breast cancer or metastatic colorectal cancer using a nonlinear mixed-effects modeling approach. Clinically relevant covariates were evaluated to assess their impact on exposure, and overall model performance was evaluated by prediction-corrected visual predictive checks.

Results: A two-compartment pharmacokinetic model with linear elimination and first-order absorption preceded by a lag time adequately described tucatinib pharmacokinetic profiles in 151 healthy participants and 132 patients. Tumor type was identified as a significant covariate affecting tucatinib bioavailability and clearance, resulting in a 1.2-fold and 2.1-fold increase in tucatinib steady-state exposure (area under the concentration-time curve) in HER2+ metastatic colorectal cancer and HER2+ metastatic breast cancer, respectively, compared with healthy participants. No other covariates, including mild renal or hepatic impairment, had an impact on tucatinib pharmacokinetics.

Conclusions: The impact of statistically significant covariates identified was not considered clinically meaningful. No tucatinib dose adjustments are required based on the covariates tested in the final population pharmacokinetic model.

Clinical trial registration: NCT03723395, NCT03914755, NCT03826602, NCT03043313, NCT01983501, NCT02025192.

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来源期刊
CiteScore
8.80
自引率
4.40%
发文量
86
审稿时长
6-12 weeks
期刊介绍: Clinical Pharmacokinetics promotes the continuing development of clinical pharmacokinetics and pharmacodynamics for the improvement of drug therapy, and for furthering postgraduate education in clinical pharmacology and therapeutics. Pharmacokinetics, the study of drug disposition in the body, is an integral part of drug development and rational use. Knowledge and application of pharmacokinetic principles leads to accelerated drug development, cost effective drug use and a reduced frequency of adverse effects and drug interactions.
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