A Whole-Body Physiologically Based Pharmacokinetic Model for Alpha Particle Emitting Bismuth in Rats.

Abstract

Background: α particle emitting bismuth (²¹²Bi) as decay product of ²¹²Pb-labeled pharmaceuticals has been effective in targeted α particle therapy (TAT). Estimating the contribution of ²¹²Bi 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 ²¹²Bi-PBPK model was developed to describe the pharmacokinetics (PKs) of ²¹²Bi in rats. Materials and Methods: The rat ²¹²Bi-PBPK model was implemented using the modeling software SAAM II with data and parameter values from the literature. Besides other mechanisms, ²¹²Bi 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 ²¹²Bi. Results: ²¹²Bi 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. Conclusions: Kidneys are the dose-limiting organs in ²¹²Bi-based TAT. The ²¹²Bi-PBPK model is an effective tool to investigate the ²¹²Bi biodistribution in murine models. Integrating the ²¹²Bi-PBPK model into other murine and human PBPK models of α particle generators can help study the efficacy and safety of TAT.