Modeling the Effect of Daughter Migration on Dosimetry Estimates for [²²⁵Ac]Ac-DOTATATE.

Abstract

[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. 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. 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. 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.