A whole-body physiologically-based pharmacokinetic model for alpha particle emitting bismuth in rats

Introduction/Aim: alpha particle emitting bismuth (Bi-212) as decay product of Pb-212-labeled pharmaceuticals has been effective in targeted alpha particle therapy (TAT). Estimating the contribution of Bi-212 released from its chelator to the absorbed doses in nontarget tissues is challenging in TAT. Physiologically based pharmacokinetic (PBPK) modeling can help overcome this limitation. Therefore, a whole-body Bi-212-PBPK model was developed to describe the pharmacokinetics (PKs) of Bi-212 in rats. Materials and Methods: The rat Bi-212-PBPK model was implemented using the modeling software SAAM II with data and parameter values from the literature. Besides other mechanisms, Bi-212 interactions with red blood cells, high molecular weight plasma protein, and intracellular biological thiols are described. Important PK parameters were fitted to time-activity data. Absorbed dose coefficients (ADCs) were calculated for injecting 0.774 fmol of Bi-212. Results: Bi-212 uptake rates of liver, bone, small intestine, bone marrow, skin, and muscle were (0.86 +/- 0.13), (3.85 +/- 0.63), (0.27 +/- 0.05), (1.44 +/- 0.29), (0.04 +/- 0.01), and (0.007 +/- 0.007) per min with corresponding ADCs of 0.09, 0.03, 0.03, 0.07, 0.01, and 0.003 mGy/kBq, respectively. An ADC of 0.70 mGy/kBq was determined for kidneys. Conclusion: Kidneys are the dose-limiting organs in Bi-212-based TAT. The Bi-212-PBPK model is an effective tool to investigate the Bi-212 biodistribution in murine models. Integrating the Bi-212-PBPK model into other murine and human PBPK models of alpha particle generators can help study the efficacy and safety of TAT.