Extrapolating organ and tumor doses for 225Ac-PSMA-I&T radionuclide therapy in patients with mCRPC

Introduction: Clinical implementation of actinium-225 as a therapeutic radionuclide requires consideration of the radiation dose profile for not only patient safety, but also meaningful study design and regulatory approvals. However, imaging-based dosimetry for actinium-225 radiopharmaceuticals is near impossible to calculate directly due to low injected activities and low gamma count statistics. The aim of this work was to indirectly estimate organ and tumor doses for ²²⁵Ac-PSMA-I&T by extrapolating kinetic activity data from ¹⁷⁷Lu-PSMA-I&T in patients with mCRPC.

Methods: Tumor and organ time-activity curves based on whole-body planar scintigraphy for 14 patients with mCRPC obtained after their first cycle of ¹⁷⁷Lu-PSMA-I&T were extrapolated from the 6.7 day half-life of ¹⁷⁷Lu to the 9.9 day half-life of ²²⁵Ac. Source organs included kidneys, liver, salivary glands (using counts from delineated bilateral parotid glands), body remainder, and tumor targets. All subsequent curve-fitting, integration, and dose calculation was performed using OLINDA/EXM v. 2.0 with the adult male phantom model for organs and the sphere model for tumor self-irradiated doses. Time activity curves with 3 time points were fit with mono-exponential functions, and bi-exponential functions were used to fit curves with at least 4 time points. All daughter radionuclides of ²²⁵Ac were assumed to decay instantaneously with no translocation, and a relative biologic effectiveness of 5 was assumed for alpha particles.

Results: The mean whole-body effective dose for ²²⁵Ac-PSMA-I&T was 37.1 mSv/MBq. Therefore, for administration of 8 MBq (0.22 mCi) ²²⁵Ac-PSMA-I&T, the whole-body effective dose is 0.30 Sv ± 0.18 Sv for a single cycle. The highest equivalent dose, assuming a relative biologic effectiveness of 5, is observed in the kidneys (4.91 Sv), followed by osteogenic cells (2.4 Sv), salivary glands (1.85 Sv), and liver (0.54 Sv). For a potential total of 4 cycles of ²²⁵Ac-PSMA-I&T, the estimated cumulative kidney dose is 19.6 Sv, followed by 9.6 Sv in osteogenic cells, 7.4 Sv in salivary glands, and 2.2 Sv in the liver. A total of 37 tumors were analyzed, yielding a mean overall dose of 4.3 Gy/GBq ± 2.6 Gy/GBq, with significant variation both within and between patients. This represents a net 27% increase in tumor dose for ²²⁵Ac over ¹⁷⁷Lu estimates.

Conclusions: Growing interest in the widespread application of actinium-225-based radiopharmaceuticals necessitates a better understanding of the dosimetry profile. In this work, we extrapolated ²²⁵Ac-PSMA-I&T doses based on prior ¹⁷⁷Lu dosimetry data in patients with mCRPC. Average doses in the kidneys and salivary glands were 0.61 ± 0.2 Sv/MBq and 0.2 ± 0.1 Sv/MBq, respectively. The average theoretical tumor dose was 4.3 ± 2.6 Gy/GBq, representing a 27% increase compared with estimates from ¹⁷⁷Lu-PSMA-I&T patients.

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