PO.ET02.07 · 实验与分子治疗
给予纳米免疫偶联物贝伐珠单抗后nab-紫杉醇的群体药代动力学
Population pharmacokinetics of nab-paclitaxel following administration of a nano-immunoconjugate with bevacizumab
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
引言。本研究旨在表征在向不可切除的IV期黑色素瘤或妇科肿瘤患者给予纳米免疫偶联物nab-紫杉醇-贝伐珠单抗后nab-紫杉醇的群体药代动力学(PopPK)(NCT02020707)。核心目的是表征群体平均药物浓度-时间曲线,理解药物浓度的变异性,并识别可解释紫杉醇血浆清除率差异的因素。此外,我们还试图探究纳米免疫偶联物制剂对紫杉醇清除率的影响。
方法。使用Pumas AI(一款整合机器学习方法的先进药代动力学软件程序),利用采集自29名受试者的浓度-时间数据(681次浓度测量)进行PopPK分析。患者接受75-175 mg/m²(总剂量160-360 mg)。基于静脉给药后血浆浓度呈现的双相下降,将数据拟合至二室模型。该模型的一个关键要求是纳入可饱和消除以准确描述药物的处置。实施了全面的建模工作流程,从基础模型(混合型与非线性清除)开始,随后依次加入协变量(年龄、性别、BSA、肿瘤、周期)。应用简约原则(Parsimony Principle)以选择最合适的模型。
结果。紫杉醇清除率和分布容积的群体估计值分别为41.7 L/hr和312 L。分析发现,与已发表的单独nab-紫杉醇数据相比(21.1或25 L/h/m²;Sparreboom等,CCR 11:4136,2005以及Ando等,CCP 69:457,2012),紫杉醇清除率更高。纳入BSA和性别的协变量模型为最佳模型。BSA每增加2 m²,线性清除率(CL)增加6.9%。女性的CL比男性低16.6%,这成功地表征了受试者亚组之间PK的系统性差异。
结论。通过纳米免疫偶联物制剂给予nab-紫杉醇导致紫杉醇清除率增加,与治疗性抗体已知的清除机制一致。患者间药物清除率的差异主要归因于协变量BSA和性别。这些发现对于确定安全有效的给药方案以及为未来临床模拟提供信息至关重要。
查看英文原文 English abstract
Introduction. This study aimed to characterize the population pharmacokinetics (PopPK) of nab-paclitaxel following the administration of the nano-immunoconjugate nab-paclitaxel-bevacizumab to patients with unresectable stage IV melanoma or gynecological cancers (NCT02020707). The core objective was to characterize the population mean drug concentration-time profile, understand the variability in drug concentrations and identify factors that explain differences in paclitaxel plasma clearance. Also, we sought to explore the impact of the nano-immunoconjugate formulation on paclitaxel clearance.
Methods. Using Pumas AI - an advanced pharmacokinetic software program, integrating Machine Learning methods - a PopPK analysis was conducted using concentration-time data collected from 29 subjects, (681 concentration measurements). Patients received 75 - 175 mg/m 2 (total dose, 160 - 360 mg). Data were fitted to a 2-compartment model based biphasic decline observed in plasma concentration following intravenous administration. A critical requirement for the model was the inclusion of saturable elimination to accurately describe the drug's disposition. A comprehensive modeling workflow was implemented, starting with base models (mixed vs. non-linear clearance), followed by the sequential addition of covariates (Age, Sex, BSA, Tumor, Cycle). The Parsimony Principle was applied to select the most appropriate model.
Results. Population estimates for paclitaxel clearance and volume of distribution were 41.7 L/hr and 312 L, respectively. The analysis found paclitaxel clearance higher when compared with published data for nab-paclitaxel alone (21.1 or 25 L/h/m 2 ; Sparreboom et al, CCR 11:4136, 2005 and Ando et al, CCP 69:457, 2012). A covariate model incorporating BSA and Gender is the best. For every 2 m 2 increase in BSA, linear clearance (CL) increases by 6.9%. Females have 16.6% lower CL than males, which successfully characterized systematic differences in PK between subgroups of subjects.
Conclusion. The administration of nab-paclitaxel via the nano-immunoconjugate formulation led to increased clearance for paclitaxel consistent with known clearance mechanisms for therapeutic antibodies. The differences in drug clearance among patients were primarily attributable to covariates BSA and gender. These findings are crucial for identifying safe and effective dosing regimens and informing future clinical simulations.
利益披露 Disclosure
M. B. Chama, None.
M. S. Block,
Sorrento Therapeutics ).
Alkermes ).
Bristol-Myers Squibb ).
Genentech ).
Merck ).
nFerence ).
Perspective Therapeutics ).
Regeneron ).
TILT Biotherapeutics ).
Transgene ).
V. J. Suman, None..
J. M. Reid, None.