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Modeling the Effect of Daughter Migration on Dosimetry Estimates for [225Ac]Ac-DOTATATE
Stephen Tronchin1, Jake Forster2, Kevin Hickson3
1Department of Physics, The University of Adelaide, Adelaide, South Australia, Australia.
Purpose:
[225Ac]Ac-DOTATATE is a promising treatment option for patients with neuroendocrine tumors. A concern with 225Ac is that the decay energy can break the bond to the targeting vehicle, producing free daughter radionuclides in the body. Daughter migration is generally not considered in clinical dosimetry, and therefore its effect needs to be studied.
Methods And Materials:
A compartment model for 225Ac and its daughters was developed, where each daughter isotope was assigned unique transfer coefficients. The model was applied to [225Ac]Ac-DOTATATE. Computer simulations were performed in Python for 2 scenarios: (1) the daughters decay at the site of [225Ac]Ac-DOTATATE decay; and (2) the daughters have unique biokinetics, where each decay of [225Ac]Ac-DOTATATE releases 221Fr off the DOTATATE peptide. Two extreme cases concerning intracellular degradation of [225Ac]Ac-DOTATATE were also examined: 1 in which it remains intact inside the tumor cells, and 1 with complete degradation followed by free 225Ac released back to plasma. Normal organ and tumor absorbed doses were determined in each case. In addition, the model-calculated cumulated activities of 221Fr and 213Bi were compared with recent measurements from a clinical trial.
Results:
When modeling the unique daughter kinetics, the average absorbed dose to the kidneys and tumor was 517 (95% CI, 413-622) and 577 (95% CI, 134-1020) mGy/MBq, respectively, with daughter migration resulting in an average increase in the kidney dose of 10.2% (95% CI, 7.9%-12.5%), and an average decrease in the tumor dose of 22.9% (95% CI, 16.3%-29.4%). The model scenario including free 225Ac showed improved agreement with clinical trial data, specifically for the liver, suggesting a fraction of free 225Ac is produced in patients following the administration of [225Ac]Ac-DOTATATE.
Conclusions:
When performing dosimetry for [225Ac]Ac-DOTATATE, our study found that if daughter migration is ignored, the kidney dose is underestimated by ∼10%, and the tumor dose is overestimated by ∼23%. For accurate dosimetry, daughter biokinetics should be considered.
