Multi-Cycle Dosimetry of the Albumin-Binding Prostate-Specific Membrane Antigen Ligand [177Lu]Ludotadipep in Metastatic Androgen Pathway Modulator-Resistant Prostate Cancer with Adjusted Red Marrow Modeling

Purpose: This dosimetry study aimed to evaluate the organ-absorbed doses and safety profile of multiple doses of [177Lu]Ludotadipep, a novel PSMA-targeted radiopharmaceutical with an albumin-binding motif, in patients with metastatic androgen pathway modulator-resistant (mAPMR) prostate cancer. Methods: Twenty patients received a total of 68 cycles of [177Lu]Ludotadipep (3.70 GBq/cycle, up to six cycles, 8-week intervals), and dosimetry analysis was done for 67 cycles. Organ-absorbed doses were estimated using planar and SPECT/CT imaging and blood-based methods. Red marrow dose was calculated using a red marrow-to-blood activity concentration ratio (RMBLR) derived from a hematocrit-adjusted model for large molecules and cross-checked by comparison with data derived from quantitative SPECT/CT images and blood samples. Results: The hematocrit-adjusted RMBLR of 0.28 was consistent with physiologic expectations for albumin-bound agents for marrow dosimetry. The highest absorbed dose coefficients in the first cycle were in the salivary glands and kidneys (1.22 ± 0.530 and 0.674 ± 0.330 Gy/GBq, respectively), while the red marrow dose (0.0533 ± 0.0115 Gy/GBq) was lower. Summing the cycle-specific mean absorbed dose coefficients and multiplying by 3.70 GBq per cycle yielded projected six-cycle absorbed doses of 18.1 Gy for kidneys, 15.3 Gy for salivary glands, and 1.28 Gy for red marrow, all of which were below the reference dose constraints. Salivary gland dose coefficients declined significantly over repeated cycles (p  <  0.001), possibly from radiation-induced tissue damage. Conclusion: [177Lu]Ludotadipep demonstrates a favorable dosimetric safety profile across multiple cycles, up to six cycles. Application of an appropriately adjusted RMBLR for albumin-binding behavior allowed for reproducible red marrow dose estimation.