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

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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.