Abdollahi Hamid, Fele-Paranj Ali, Rahmim Arman
Department of Radiology, University of British Columbia, Vancouver, BC V5Z 1M9, Canada.
Department of Integrative Oncology, BC Cancer Research Institute, Vancouver, BC V5Z 1L3, Canada.
Cancers (Basel). 2024 Sep 10;16(18):3120. doi: 10.3390/cancers16183120.
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). 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. 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. 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.
研究基于生理学的药代动力学（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（RPT）中的物理、生物学和统计学指标的影响。使用经过临床验证的PBPK模型，基于各种模型参数生成肿瘤、唾液腺和肾脏的实际时间-活性曲线（TAC）。这些TAC用于计算TAC下面积（AUC）、剂量、生物有效剂量（BED）和品质因数BED（fBED）。评估了这些参数对放射生物学、药代动力学、时间和统计学特征的影响。操纵PBPK参数在四种不同的BED模型中显著影响AUC、剂量、BED和fBED结果。较高的结合率增加了肿瘤的AUC、剂量和BED值，对非靶器官的影响最小。内化率增加降低了肿瘤和肾脏的AUC和剂量。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升高增强了肿瘤的摄取和有效性。更大的肿瘤体积需要进行剂量学调整以维持疗效。将肿瘤释放率设为零增强了结合率和内化率的影响，增强了肿瘤靶向性，同时将对唾液腺和肾脏的影响降至最低。优化PBPK参数可提高靶向PSMA的镥-177标记RPT的疗效，为个性化和有效的治疗方案提供见解，以最小化毒性并改善治疗结果。
