Study of the dependence of the pharmacokinetic and dosimetric characteristics of Re-188-labeled phosphonic acids on their structure in the rat body based on compartmental modeling

Abstract

Phosphonic acids labeled with radionuclide Re-188 are the most promising radiopharmaceuticals for radionuclide therapy of bone metastases. The aim of the work is to develop a compartment mathematical model of the kinetics of Re-188-labeled phosphonic acids in the body of intact rats and calculate on its basis the pharmacokinetic and dosimetric characteristics of these radiopharmaceuticals with different chemical structures. The objects of the study were four radiopharmaceuticals containing from two to five phosphonic groups. To identify the model parameters and calculate the characteristics, quantitative data on the bio-distribution of 188Re-labeled phosphonic acids in the body of intact rats were used. A compartment model of kinetics has been developed and two approaches to the identification of its transport constants have been proposed – through the residual functional and using approximation by monoexponential functions. According to pharmacokinetic modeling, all studied radiopharmaceuticals selectively accumulate in bone tissues, and the chemical structure of phosphonic acids affects their accumulation and excretion. According to the level of accumulation of activity in the skeleton, the structures of radiopharmaceuticals can be arranged in descending order: five phosphonic groups > two > four. At the same time, the radiopharmaceutical with two phosphonic groups is removed from the bone tissues most slowly, which is its advantage. The rate of removal of radiopharmaceuticals from the blood and other organs is on average three times higher than from bone tissue. The elimination of radioactivity from the body occurs mainly through renal clearance. The highest values of absorbed doses are formed in the bone tissues (thighs, ribs, skull, spine) and the organ of excretion – the kidneys. At the same time, the maximum values of absorbed doses in bone tissues were obtained for radiopharmaceuticals with five and two phosphonic groups, which together with their pharmacokinetic properties allows them to be considered as promising osteotropic radiopharmaceuticals for the treatment of bone metastases.