Individualized radioligand therapy planning based on quantitative PET/MRI and PBPK/PD modelling: proof of concept in a preclinical setting

前列腺癌是西半球最常见的癌症，也是男性癌症死亡的第二大原因。用Lu-177标记的前列腺特异性膜抗原(PSMA)特异性配体有望用于治疗转移性、抗去势的前列腺癌(MCRPC)。最近发表了一些研究，描述了用Lu-177标记的PSMA特异性配体进行放射配基治疗(RLT)的有效性和安全性。然而，尽管mCRPC患者的受体密度、总肿瘤质量和肾功能不同，但大多数标准活性和配基数量是被给予的。正如动物实验和我们的人体模型研究所证明的那样，这导致了本质上不同的药代动力学，从而吸收了对肿瘤和危险器官的剂量。考虑到患者的具体参数，允许量化最佳配基数量和活性的个体方法最有可能进一步提高疗效并减少副作用。最近，我们已经证明了基于图像信息的基于生理的药代动力学和动力学(PBPK/PD)建模方法在个体化治疗中非常有前途。我们开发了一个基于治疗前后正电子发射断层扫描(PET/CT)的时间-活动数据和肿瘤体积变化的PBPK/PD模型，以及mCRPC患者治疗前后的测量数据。尽管有大量的数据和模拟研究，但还没有进行评估这种方法的前瞻性临床研究。一个主要的障碍是缺乏显示这种方法的有效性和可行性的临床前数据。这些数据对于证明1/2期前瞻性临床研究的合理性至关重要。因此，该项目的总体目标是在受控的小动物实验环境中证明在PET/MR引导下使用Lu-177-PSMA配体进行个体化放射配基治疗的可行性、有效性和安全性。本项目的具体目标是：·建立PSMA结合配体rhPSMA7.3的小鼠PBPK/PD模型，该模型包含所有相关的药代动力学和动力学机制。·建立包含模型开发和验证所需所有测量的测量协议。·验证PET/MR引导的放射配基治疗的概念，使用同一配体进行成像(标记为F-18)和治疗(标记为Lu-177)。这一概念被定义为：1.通过个体化给药配体的数量和活性来改善治疗指数(肿瘤/肾床比)；2.基于治疗前的PET/MR成像和PBPK/PD模型预测肿瘤体积变化/肿瘤生长延迟。

Prostate cancer is the most common cancer and the second leading cause of cancer death in men in the western hemisphere. Prostate-specific membrane antigen (PSMA)-specific ligands labelled with Lu-177 are promising for the treatment of patients with metastatic, castration-resistant prostate cancer (mCRPC). A number of studies have recently been published describing the efficacy and safety of Radioligand Therapy (RLT) with Lu-177-labelled PSMA-specific ligands. However, mostly standard activities and ligand amounts are administered despite different receptor densities, total tumour masses and kidney function in mCRPC patients. This leads to substantially different pharmacokinetics and thus absorbed doses to tumours and organs at risk, as demonstrated in animal experiments and our human model¬ling studies. An individual approach that allows the quantification of the optimal ligand amount and activity taking into account patient specific parameters would most likely further increase the efficacy and reduce side effects. Recently we have demonstrated that image-informed physiologically based pharmacokinetic and -dynamic (PBPK/PD) modelling approaches are very promising for individualization of treatment. We developed a PBPK/PD model based on time-activity data and tumour volume changes from positron emission tomography/computed tomography (PET/CT) prior and after therapy and peri-therapeutic measurements from mCRPC patients.Despite this plethora of data and simulation studies, no prospective clinical studies evaluating this approach have been conducted yet. One major obstacle is missing preclinical data showing the efficacy and feasibility of this approach. Such data would be of paramount importance to justify a prospective clinical phase 1/2 study. Therefore, the overall goal of the project is to prove the feasibility, efficacy and safety of PET/MR-guided individualized radioligand therapy with Lu-177-PSMA ligands within a controlled experimental small animal setting.The specific aims of this project are:•To develop a murine PBPK/PD model for the PSMA binding ligand rhPSMA7.3 that includes all relevant pharmacokinetic and -dynamic mechanisms. •To establish a measurement protocol that contains all required measurements for model development and validation. •To validate the concept of PET/MR-guided radioligand therapy using the same ligand for imaging (labelled with F-18) and therapy (Lu-177 labelled ). This concept is defined as 1.improving the therapeutic index (tumour-to-kidney BED ratio) by individualizing the administered ligand amount and activity and 2.predicting the tumour volume changes/tumour growth delay based on pre-therapeutic PET/MR imaging and a PBPK/PD model.