文章：

基于模型的放射性药物疗法优化：PBPK模型参数对177Lu-PSMA疗法中物理、生物及统计学指标影响的研究

Model-Informed Radiopharmaceutical Therapy Optimization: A Study on the Impact of PBPK Model Parameters on Physical, Biological, and Statistical Measures in177Lu-PSMA Therapy

原文发布日期：10 September 2024

DOI: 10.3390/cancers16183120

类型: Article

开放获取: 是

英文摘要：

Purpose:To investigate the impact of physiologically based pharmacokinetic (PBPK) parameters on physical, biological, and statistical measures in lutetium-177-labeled radiopharmaceutical therapies (RPTs) targeting the prostate-specific membrane antigen (PSMA).Methods:Using a clinically validated PBPK model, realistic time–activity curves (TACs) for tumors, salivary glands, and kidneys were generated based on various model parameters. These TACs were used to calculate the area-under-the-TAC (AUC), dose, biologically effective dose (BED), and figure-of-merit BED (fBED). The effects of these parameters on radiobiological, pharmacokinetic, time, and statistical features were assessed.Results:Manipulating PBPK parameters significantly influenced AUC, dose, BED, and fBED outcomes across four different BED models. Higher association rates increased AUC, dose, and BED values for tumors, with minimal impact on non-target organs. Increased internalization rates reduced AUC and dose for tumors and kidneys. Higher serum protein-binding rates decreased AUC and dose for all tissues. Elevated tumor receptor density and ligand amounts enhanced uptake and effectiveness in tumors. Larger tumor volumes required dosimetry adjustments to maintain efficacy. Setting the tumor release rate to zero intensified the impact of association and internalization rates, enhancing tumor targeting while minimizing the effects on salivary glands and kidneys.Conclusions:Optimizing PBPK parameters can enhance the efficacy of lutetium-177-labeled RPTs targeting PSMA, providing insights for personalized and effective treatment regimens to minimize toxicity and improve therapeutic outcomes.

摘要翻译： 

目的：探讨基于生理的药代动力学（PBPK）参数对靶向前列腺特异性膜抗原（PSMA）的镥-177标记放射性药物治疗（RPTs）中物理、生物及统计学指标的影响。 方法：采用经临床验证的PBPK模型，基于不同模型参数生成肿瘤、唾液腺及肾脏的真实时间-活度曲线（TACs）。利用这些TACs计算曲线下面积（AUC）、剂量、生物有效剂量（BED）及优值生物有效剂量（fBED），并评估这些参数对放射生物学、药代动力学、时间及统计学特征的影响。 结果：调整PBPK参数显著影响了四种不同BED模型下的AUC、剂量、BED及fBED结果。较高的结合速率增加了肿瘤的AUC、剂量和BED值，而对非靶器官影响甚微。内化速率升高降低了肿瘤和肾脏的AUC与剂量。较高的血清蛋白结合率降低了所有组织的AUC和剂量。肿瘤受体密度和配体量的增加提升了肿瘤的摄取和治疗效果。较大的肿瘤体积需调整剂量测定以维持疗效。将肿瘤释放速率设为零可增强结合速率与内化速率的影响，从而提升肿瘤靶向性，同时减轻对唾液腺和肾脏的作用。 结论：优化PBPK参数可提升靶向PSMA的镥-177标记RPTs的疗效，为制定个性化、高效的治疗方案提供依据，以降低毒性并改善治疗效果。

原文链接：

Model-Informed Radiopharmaceutical Therapy Optimization: A Study on the Impact of PBPK Model Parameters on Physical, Biological, and Statistical Measures in177Lu-PSMA Therapy