A compartmental model of mouse thrombopoiesis and erythropoiesis to predict bone marrow toxicity after internal irradiation

Abstract

In targeted radionuclide radiotherapy, the relationship between bone marrow (BM) toxicity and absorbed dose seems to be elusive. A compartmental model of mouse thrombopoiesis and erythropoiesis was set up to predict the depletion of hematopoietic cells as a function of the irradiation dose delivered to BM by injected radiopharmaceuticals. All simulated kinetics were compared with experimental toxicity for several stages of differentiation of the 2 hematopoietic lineages. Methods: C57BL/6 mice were injected either with 18 FNa (37 and 60 MBq), a bone-seeking agent, or with saline. BMmean absorbed doses were calculated according to the MIRD formalism from small-animal PET/CT images. Hematologic toxicity was monitored over time, after 18 FNa injection, by studying BM progenitors and precursors in addition to blood cells. The compartmental model takes into account the pharmacokinetics of the compound, in addition to cellular kinetics and cell radiosensitivities for the 2 studied lineages. Results: Because biodistribution studies showed an uptake of 18 FNa in bones, the skeleton was considered as the principal source organ of BM irradiation. The time-activity curve obtained from validated quantification of PET/CT images allowed for the calculation ofmean absorbed doses to the wholeBMof 2.1 and 3.4 Gy for 18 FNa injections of 37 and 60MBq, respectively.Concerning hematologic toxicity, themodel was in good agreement for the 2 absorbed doses with experimental measurements of cell depletion for platelets, progenitors, and precursors within the BM in terms of time to nadir, depletion intensity, and timeto recovery. The same agreement was obtained for red blood cells and their precursors. Model predictions demonstrated that BM toxicity was in correlation with the mean absorbed dose as higher depletions at nadir and longer delays to recovery were noticed for 3.4 Gy than for 2.1 Gy. Conclusion: The developed compartmental model of thrombopoiesis and erythropoiesis in a BMtoxicity context, after internal irradiation, allowed for the prediction of cell kinetics of BM progenitors, precursors, and mature blood cells in a dose-dependent manner. This model could therefore be used to predict hematologic toxicity in preclinical internal radiotherapy to study the dose-response relationship. COPYRIGHT © 2014 by the Society of Nuclear Medicine and Molecular Imaging, Inc.