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去势抵抗性前列腺癌（mCRPC）患者。最近发表了许多研究，描述了使用Lu-177标记的PSMA特异性配体的放射性配体治疗（RLT）的疗效和安全性。然而，尽管mCRPC患者的受体密度、总肿瘤质量和肾功能不同，但大多数情况下给予标准活性和配体量。这导致了显著不同的药代动力学，从而导致了肿瘤和危险器官的吸收剂量，如动物实验和我们的人体建模研究所证明的。考虑到患者特定参数，允许定量最佳配体量和活性的个体方法将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，基于图像的生理药代动力学和动力学（PBPK/PD）建模方法是非常有前途的个性化治疗。我们开发了一个PBPK/PD模型的基础上的时间活动数据和肿瘤体积的变化，从正电子发射断层扫描/计算机断层扫描（PET/CT）治疗前后和围治疗期测量mCRPC patients.Despite这过多的数据和模拟研究，还没有前瞻性的临床研究评估这种方法进行。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。这些数据对于证明前瞻性临床I/II期研究的合理性至关重要。因此，本项目的总体目标是在受控的实验小动物环境中证明PET/MR引导的使用Lu-177-PSMA配体的个体化放射性配体治疗的可行性、有效性和安全性。本项目的具体目标是：·开发PSMA结合配体rhPSMA 7.3的鼠PBPK/PD模型，其包括所有相关的药代动力学和动力学机制。·建立一个包含模型所需所有测量的测量协议 开发和验证。·验证PET/MR引导的放射性配体治疗的概念，使用相同的配体用于成像（用F-18标记）和治疗（Lu-177标记）。这一概念被定义为：1.通过个体化治疗， 施用的配体量和活性，以及2.基于治疗前的肿瘤体积变化/肿瘤生长延迟， PET/MR成像和PBPK/PD模型。

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.