Dosimetric impact of Ac-227 in accelerator-produced Ac-225 for alpha-emitter radiopharmaceutical therapy of patients with hematological malignancies: a pharmacokinetic modeling analysis

BACKGROUND: Actinium-225 is an alpha-particle emitter under investigation for use in radiopharmaceutical therapy. To address limited supply, accelerator-produced (225)Ac has been recently made available. Accelerator-produced (225)Ac via (232)Th irradiation (denoted (225/7)Ac) contains a low percentage (0.1–0.3%) of (227)Ac (21.77-year half-life) activity at end of bombardment. Using pharmacokinetic modeling, we have examined the dosimetric impact of (227)Ac on the use of accelerator-produced (225)Ac for radiopharmaceutical therapy. We examine the contribution of (227)Ac and its daughters to tissue absorbed doses. The dosimetric analysis was performed for antibody-conjugated (225/7)Ac administered intravenously to treat patients with hematological cancers. Published pharmacokinetic models are used to obtain the distribution of (225/7)Ac-labeled antibody and also the distribution of either free or antibody-conjugated (227)Th. RESULTS: Based on our modeling, the tissue specific absorbed dose from (227)Ac would be negligible in the context of therapy, less than 0.02 mGy/MBq for the top 6 highest absorbed tissues and less than 0.007 mGy/MBq for all other tissues. Compared to that from (225)Ac, the absorbed dose from (227)Ac makes up a very small component (less than 0.04%) of the total absorbed dose delivered to the 6 highest dose tissues: red marrow, spleen, endosteal cells, liver, lungs and kidneys when accelerator produced (225/7)Ac-conjugated anti-CD33 antibody is used to treat leukemia patients. For all tissues, the dominant contributor to the absorbed dose arising from the (227)Ac is (227)Th, the first daughter of (227)Ac which has the potential to deliver absorbed dose both while it is antibody-bound and while it is free. CONCLUSIONS: These results suggest that the absorbed dose arising from (227)Ac to normal organs would be negligible for an (225/7)Ac-labeled antibody that targets hematological cancer.