Use of Monte Carlo simulations with a realistic rat phantom for examining the correlation between hematopoietic system response and red marrow absorbed dose in Brown Norway rats undergoing radionuclide therapy with¹⁷⁷Lu- and⁹⁰Y-BR96 mAbs

Abstract

Purpose: Biokinetic and dosimetry studies in laboratory animals often precede clinical radionuclide therapies in humans. A reliable evaluation of therapeutic efficacy is essential and should be based on accurate dosimetry data from a realistic dosimetry model. The aim of this study was to develop an anatomically realistic dosimetry model for Brown Norway rats to calculate S factors for use in evaluating correlations between absorbed dose and biological effects in a preclinical therapy study. Methods: A realistic rat phantom (Roby) was used, which has some flexibility that allows for a redefinition of organ sizes. The phantom was modified to represent the anatomic geometry of a Brown Norway rat, which was used for Monte Carlo calculations of S factors. Kinetic data for radiolabeled BR96 monoclonal antibodies were used to calculate the absorbed dose. Biological data were gathered from an activity escalation study with90Y‐ and 177Lu‐labeled BR96 monoclonal antibodies, in which blood cell counts and bodyweight were examined up to 2 months follow‐up after injection. Reductions in white blood cell and platelet counts and declines in bodyweight were quantified by four methods and compared to the calculated absorbed dose to the bone marrow or the total body. Results: A red marrow absorbed dose‐dependent effect on hematological parameters was observed, which could be evaluated by a decrease in blood cell counts. The absorbed dose to the bone marrow, corresponding to the maximal tolerable activity that could safely be administered, was determined to 8.3 Gy for177Lu and 12.5 Gy for 90Y. Conclusions: There was a clear correlation between the hematological effects, quantified with some of the studied parameters, and the calculated red marrow absorbed doses. The decline in body weight was stronger correlated to the total body absorbed dose, rather than the red marrow absorbed dose. Finally, when considering a constant activity concentration, the phantom weight, ranging from 225 g to 300 g, appeared to have no substantial effect for the estimated absorbed dose.

Development of computational small animal models and their applications in preclinical imaging and therapy research

“…21) and models of Brown Norway rat. 45 More recently, Xie and Zaidi 47,48 devised a series of voxel rat models at various ages, and with different degrees of emaciation and obesity by modifying the original ROBY model. Figure 7 shows the developed mild, moderate, severely emaciated, and the obese rat models in comparison to the normal-weight rat model.…”

“…Databases of AFs and S-values for animals, such as mouse, rat, frog, and canine, of monoenergetic photons and electrons and common radionuclides including F-18, P-32, Cu-64, Y-90, In-111, I-124, I-131, Sm-153, Pm-149, Ho-166, Lu-177, and Re-188, have been reported by various groups. 11,15,17,18,21,24,27,33,39,45,46,49,53,[78][79][80][81][82] These were largely adopted for calculation of organ absorbed dose and dosimetry of radionuclide-labeled compounds in preclinical experiments. [83][84][85][86][87][88][89][90][91][92][93][94][95] These computational models were also integrated in comparative Monte Carlo-based simulations studies investigating patterns of uptake and biodistribution data of radiopharmaceuticals for the purpose of dose estimation in molecular radiotherapy and diagnostic nuclear medical imaging procedures.…”

Intratherapeutic Biokinetic Measurements, Dosimetry Parameter Estimates, and Monitoring of Treatment Efficacy Using Cerenkov Luminescence Imaging in Preclinical Radionuclide Therapy

“…Usually, the biokinetics are evaluated with ex vivo measurements of groups of animals at different time points, followed by a dosimetry calculation relying on the biokinetics data (1). This evaluation is usually done before treatment to obtain a theoretic therapeutic window to guide the researchers (2).…”

Effect of emaciation and obesity on small-animal internal radiation dosimetry for positron-emitting radionuclides

“…However, there is an intrinsic variability in the total body weight of rats because of differences between specimens. Moreover, in some preclinical research studies, the weight of laboratory animals used in longitudinal studies can be modified by emaciation or obesity because of secondary effects of drugs, radiation therapy or chemotherapy and the use of dietary or fat regimes [23][24][25][26][27][28]. In adult rats older than 250-300 days, the increase in weight, referred to as adult 'growth' [29], has been reported to be due mostly to fat deposition.…”