Preclinical Physiologically Based Pharmacokinetic Modeling of PSMA Radioligands: Demonstrating Nonspecific Retention and Reversible Albumin-Binding Effects

Radiopharmaceutical therapy with prostate-specific membrane antigen (PSMA) radioligands has emerged as a promising treatment modality for metastatic androgen pathway modulator–resistant prostate cancer (formerly metastatic castration-resistant prostate cancer). Physiologically based pharmacokinetic (PBPK) modeling has been applied in clinical studies of PSMA radioligands. However, clinical models are necessarily simplified because of sparse patient data, which may mask important pharmacokinetic processes. The aim of this study was to perform PBPK modeling on comprehensive preclinical data and identify previously neglected dynamics of PSMA radioligands with translation relevance. Methods: Biodistribution and albumin-binding affinity data were previously obtained for the 2 PSMA radioligands [177Lu]Lu-PSMA-617 and [177Lu]Lu-PSMA I&T and the 3 albumin-binding PSMA radioligands [177Lu]Lu-SibuDAB, [177Lu]Lu-PSMA-ALB-53, and [177Lu]Lu-PSMA-ALB-56. A baseline, preclinical PBPK model was built using a widely studied radioligand PBPK model structure. Three types of modifications to the baseline model were developed: nonspecific retention in PSMA-negative tissues and kidneys, change from an irreversible to a reversible albumin-binding model, and albumin-bound fraction implementation. Models with modification combinations were built, and regressions were performed against the biodistribution data. The modifications were evaluated on the regression performances, and simulations of the fitted models were compared with clinically established baseline regressions through time-integrated activity (TIA) ratios. Results: For all radioligands, incorporating nonspecific retention markedly improved the corrected Akaike information criterion (AIC). The reversible albumin-binding model showed improved AIC for all albumin-binding radioligands. The implementation of albumin-bound fractions degraded the AIC but showed minor impact on fits. With nonspecific retention, substantial increases in TIAs were observed for PSMA-negative organs, particularly for the dose-limited organ red marrow where TIA ratios reached 3.0, 1.5, and 1.6 for [177Lu]Lu-PSMA-617, [177Lu]Lu-PSMA I&T, and [177Lu]Lu-SibuDAB, respectively. TIAs for PSMA-positive tissues and kidneys remained relatively stable. Conclusion: This preclinical study demonstrated that disregarding nonspecific retention led to marked underestimation of doses to PSMA-negative tissues such as in the radiosensitive red marrow. The models with reversible albumin-binding further improved the regressions for the albumin-binding radioligands but had limited impact on TIA estimates. By integrating these mechanisms, preclinical PBPK models provide novel insights into radioligand kinetics and can inform the refinement of clinical PBPK models toward safer and more individualized PSMA radiopharmaceutical therapy.