Physiologically based pharmacokinetic modelling of the PSMA radioligand 18F-DCFPyL to predict the tissue distribution in patients with prostate cancer
Suzanne van der Gaag (a,b), Habibe Yilmaz (c), Jan Amsu (c), Daniela E. Oprea-Lager (a,b), N. Harry Hendrikse (a,b), Imke H. Bartelink (b,d)
(a) Department of Radiology and Nuclear Medicine, Amsterdam UMC Location Vrije Universiteit Amsterdam, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands (b) Cancer Center Amsterdam, Imaging and Biomarkers, De Boelelaan 1118, 1081 HV Amsterdam, The Netherlands (c) Faculty of Science, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Universiteitsweg 99, 3584 CG Utrecht, The Netherlands (d) Department of Clinical Pharmacology and Pharmacy, Amsterdam UMC Location Vrije Universiteit Amsterdam, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands
Objectives: The most common malignancy in middle and older aged men worldwide is prostate cancer (PCa).1 Characteristic for PCa is a high expression of prostate-specific membrane antigen (PSMA) on tumor cells. Recently, the use of PSMA-targeted radioligand therapy for metastatic castration-resistant PCa has been approved by the Food and drug administration (FDA).2,3 The current fixed-dose-strategy (7400 MBq/cycle) of PSMA-radioligands may lead to inadequate response for a patient due to inter-individual variability in exposure of PSMA receptors. Therefore, personalization of treatment, in which tumor volume and PSMA receptor density are taken into account, may lead to better efficacy and less toxicity. Whole body physiological based pharmacokinetic-models (wbPBPK-models) may predict sources of variability in pharmacokinetics among patients. For PBPK modelling positron emission tomography (PET) imaging is a valuable tool to visualize and quantify the tissue distribution for the verification of a wbPBPK-model. For PSMA PET imaging, 18F-DCFPyL is a suitable radiotracer which is in clinical use because of its high affinity for PSMA receptors.
The aim of this study was to develop a wbPBPK-model to predict the tissue distribution of 18F-DCFPyL, a 18F-fluorinated diagnostic PET-radiotracer for imaging PSMA expression in patients with metastatic PCa.
Methods: We developed a wbPBPK-model including compartments for blood, tumor, prostate and healthy tissues, based on a previously published PBPK-model.4 The model was extended for accurate calculation of free and occupied PSMA receptors and to represent the renal clearance of 18F-DCFPyL. Data from a previously published prospective study of 18F-DCFPyL distribution in eight PCa patients in the Amsterdam UMC was used to validate our results.5
Model simulations were performed to determine tissue distribution of 18F-DCFPyL up to 120 minutes after intravenous injection. A prediction error (PE) was calculated to assess the predictive performance of the model to predict concentrations over the full scan window. The model was considered accurate when this performance fell within 2-fold of observed PET-derived data from all tissues of interest.
Results: The tissue distribution of 18F-DCFPyL was simulated in arterial blood, total tumor lesion, lungs and muscles. The model depicted accurate whole-body distribution, showing high tissue distribution with a mean PE for all tissues 64.96% (PE in tumors 11.68%), range 11.69 – 100.41%. The observed tumor tissue concentration-time curves of all 8 patients showed that drug uptake reached a plateau at 60 minutes after injection, which was not predicted by the wbPBPK model.
Conclusions: The final wbPBPK-model was able to adequately predict tissue distribution of 18F-DCFPyL when compared to observations from the prospective study in the first hour after injection. However, the plateau-effect at 60 minutes is currently unaccounted for the model. Future research is needed to explore further optimization of the PSMA receptor model and find causes for the overpredicted concentrations at later time points When properly validated and predictive at therapeutic dose levels, the wbPBPK-model is a potential tool to determine an individual dose for therapeutic PSMA-radioligands to treat prostate cancer.
References:
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[3] U.S. Food & Drug Administration. Updated: 23-Mar-2022, Cited: 04-Oct-2022. Available from: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pluvicto-metastatic-castration-resistant-prostate-cancer.
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