PBPK-based in silico tumor microenvironment model for ¹⁷⁷Lu-PSMA-617 therapy

Ziel/Aim The good efficacy of the targeted radionuclide-based therapy using ¹⁷⁷Lu-PSMA-617 for the treatment of metastatic castration-resistant prostate cancer has been demonstrated in several clinical studies. However, the treatment effect is still suboptimal for a significant fraction of patients and a substantial individual variance in lesion radiation dose is well known. Physiologically-based pharmaco-kinetic (PBPK) models have been established to assist the personalization of RLT. However, an in-depth insight of the interaction with tumor microenvironment is not provided. We propose an in silico approach to investigate the distribution of the radionuclide inside the tumor microenvironment through a PBPK-based convective-diffusion-reaction (CDR) model.

Methodik/Methods Dynamic distribution of ¹⁷⁷Lu-PSMA-617 was simulated by establishing an in silico model of the tumor microenvironment. The impact of the interstitial fluid pressure and velocity, the presence of hypoxic and necrotic regions, and the spatial variation of physiological parameters have been investigated. A finite-element solution of time-dependent CDR equation was implemented to calculate the distribution of ¹⁷⁷Lu-PSMA-617 at different time points post-injection. The parameters of the model were extracted from literature and optimized accordingly to the reference PBPK model. Once the activity distribution was recovered, the equivalent absorbed dose was calculated to investigate the dose in tumor microenvironment and normal organs.

Ergebnisse/Results The established model can extend the PBPK model to the spatio-temporal distribution of ¹⁷⁷Lu-PSMA-617 in the tumor microenvironment at different time points. With a proper arterial input function, the generated time-activity curves are consistent with the clinical observations. The total absorbed dose in different regions of the tumor and in critical organs can be depicted.

Schlussfolgerungen/Conclusions The proposed model can recapitulate the time course of ¹⁷⁷Lu-PSMA-617 therapy and give deep insight into the microdosimetry. Further optimization and validation of this model on experimental data is ongoing. The established in silico model provides a platform to explore different parameters for personalized optimization of ¹⁷⁷Lu-PSMA-617 therapy.

Publication History

Article published online:
08 April 2021