Population Pharmacokinetics of MYL-1402O, a Proposed Biosimilar to Bevacizumab and Reference Product (Avastin^®) in Patients with Non-squamous Non-small Cell Lung Cancer.

IF 1.9 4区医学 Q3 PHARMACOLOGY & PHARMACY European Journal of Drug Metabolism and Pharmacokinetics Pub Date : 2023-11-01 Epub Date: 2023-10-04 DOI:10.1007/s13318-023-00855-3

Joel S Owen, Russell J Rackley, Matthew A Hummel, Stefan Roepcke, Hannah Huang, Mark Liu, Tazeen A Idris, Sundara Moorthi Nainar Murugesan, Ashwani Marwah, Subramanian Loganathan, Gopinath Ranganna, Abhijit Barve, Cornelius F Waller, Mark A Socinski

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Abstract

Background and objectives: MYL-1402O is a bevacizumab (Avastin^®) biosimilar. Pharmacokinetic and safety similarity of MYL-1402O and reference Avastin^® authorized in the European Union (EU-Avastin^®) and the US (US-Avastin^®) was demonstrated in healthy subjects (phase I, NCT02469987). The key objectives of this study were to establish a population pharmacokinetic (PopPK) model on pooled data from the phase I and phase III clinical studies to assess pharmacokinetic linearity of MYL-1402O and Avastin^® across dose ranges, to assess the pharmacokinetic similarity of MYL-1402O and Avastin^® in patients with non-squamous non-small cell lung cancer (nsNSCLC), and to explore potential covariates to account for systematic sources of variability in bevacizumab exposure.

Methods: Efficacy and safety of MYL-1402O compared with EU-Avastin^® was investigated in a multicenter, double-blind, randomized, parallel-group study in patients with stage IV nsNSCLC (phase III, NCT04633564). PopPK models were developed using a nonlinear mixed effects approach (NONMEM^® 7.3.0).

Results: The pharmacokinetics of Avastin^® and MYL-1402O were adequately described with a two-compartment linear model. Fourteen covariates were found to be statistically significant predictors of bevacizumab pharmacokinectics. The impact of each covariate on area under the concentration-time curve, half-life, and maximum plasma concentration was modest, and ranges were similar between the treatment groups, MYL-1402O and EU-Avastin^®, in patients with nsNSCLC. The pharmacokinectics of bevacizumab appeared to be linear.

Conclusions: PopPK analysis revealed no significant differences between pharmacokinetics of MYL-1402O and Avastin^® in patients with nsNSCLC. The developed PopPK model was considered robust, as it adequately described bevacizumab pharmacokinetics in healthy participants and nsNSCLC patients.

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非鳞状非小细胞肺癌癌症患者中拟议的贝伐单抗生物类似物和参考产品（Avastin®）MYL-1402O的群体药代动力学。

背景和目的：MYL-1402O是一种贝伐单抗（Avastin®）生物仿制药。在健康受试者（I期，NCT02469987）中证明了MYL-1402O和欧盟（EU Avastin®）和美国（US Avastin™）授权的参考Avastin？的药代动力学和安全性相似性。本研究的主要目的是根据I期和III期临床研究的汇总数据建立群体药代动力学（PopPK）模型，以评估MYL-1402O和Avastin®在不同剂量范围内的药代动力学线性，评估MYL-1402 O和Avatin®在非鳞状非小细胞肺癌癌症患者中的药代学相似性，并探索潜在的协变量，以解释贝伐单抗暴露变异的系统来源。方法：在一项多中心、双盲、随机、平行组研究中，对MYL-1402O与EU Avastin®在IV期nsNSCLC（III期，NCT04633564）患者中的疗效和安全性进行了比较。PopPK模型是使用非线性混合效应方法（NONMEM®7.3.0）开发的。结果：阿瓦斯汀®和MYL-1402O的药代动力学用两室线性模型进行了充分描述。14个协变量被发现是贝伐单抗药物动力学的统计学显著预测因素。每个协变量对nsNSCLC患者的浓度-时间曲线下面积、半衰期和最大血浆浓度的影响是适度的，治疗组MYL-1402O和EU Avastin®之间的范围相似。贝伐单抗的药物动力学似乎是线性的。结论：PopPK分析显示，MYL-1402O和Avastin®在nsNSCLC患者中的药代动力学没有显著差异。开发的PopPK模型被认为是稳健的，因为它充分描述了贝伐单抗在健康参与者和非小细胞肺癌患者中的药代动力学。

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来源期刊

European Journal of Drug Metabolism and Pharmacokinetics 医学-药学

CiteScore

3.70

自引率

0.00%

发文量

审稿时长

>12 weeks

期刊介绍： Hepatology International is a peer-reviewed journal featuring articles written by clinicians, clinical researchers and basic scientists is dedicated to research and patient care issues in hepatology. This journal focuses mainly on new and emerging diagnostic and treatment options, protocols and molecular and cellular basis of disease pathogenesis, new technologies, in liver and biliary sciences. Hepatology International publishes original research articles related to clinical care and basic research; review articles; consensus guidelines for diagnosis and treatment; invited editorials, and controversies in contemporary issues. The journal does not publish case reports.