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

Ziel/Aim Alpha particle emitting bismuth (Bi-212/213) labelled pharmaceuticals are used in targeted alpha particle therapy (TAT) for cancer treatment. The 45.6- and 60.6-min half-lives of unconjugated Bi-213 and Bi-212 allow their redistribution in the whole body inducing toxicity to non-target tissues. Investigation of the pharmacokinetics of Bi-212/213 is required to assess the safety and efficacy of TAT. Therefore, a whole-body physiologically-based pharmacokinetic model of Bi-212 (Bi-212-PBPK) was developed to describe the pharmacokinetics of Bi-212 in rats.

Methodik/Methods The Bi-212-PBPK model was developed and implemented using the modelling software SAAM II (v2.3). The model includes main physiological mechanisms, such as blood flow, transcapillary transport and urinary excretion with parameter values from the literature. First-order kinetics are assumed to describe Bi-212 interactions with red blood cells (RBC), high molecular weight plasma protein (HWPP) and intracellular biological thiols. Model evaluation and subsequent estimation of model parameters were performed using Bi-212 biokinetic data in rats which were obtained after the intravenous administration of 0.07 fmol of Bi-212 (2.4 µCi) in blood [1].

Ergebnisse/Results Model implementation was successful and the fitted curves were good by visual inspection and R² >0.92. The association rates of Bi-212 with RBC and HWPP were 0.006 ± 0.003 and 0.18 ± 0.04 min^-1, respectively. The dissociation rates of RBC- and HWPP-conjugated Bi-212 were 0.02 ± 0.01 and 0.10 ± 0.02 min^-1, respectively. Bi-212 uptake rates by liver, small intestine, bone, bone marrow, skin and muscles cells were 0.81 ± 0.12, 0.27 ± 0.05, 0.53 ± 0.13, 1.48 ± 0.32, 0.04 ± 0.01 and 0.01 ± 0.01 min^-1.

Schlussfolgerungen/Conclusions The Bi-212-PBPK model can be an effective tool to investigate the biodistribution of Bi-212 in murine models. Integrating the Bi-212-PBPK model into other PBPK models of alpha particle generators will help to study the efficacy and safety of TAT.

• Literatur/References

• 1 Hursh JB. , et al., 131 (01) ): 116-120

Publication History

Article published online:
08 April 2021