A.V. Matveev

Dostoevsky Omsk State University (Omsk, Russia)

In Russia, two radiopharmaceuticals are currently used for radionuclide therapy of bone metastases: 89Sr-chloride and 153Sm-oxabifor. The first one has many side effects, so its use is limited. The second one is available only in clinics, its transportation to which does not take much time. Currently, the third radiopharmaceutical 188Re-solerene is undergoing clinical trials. Due to the generator method of obtaining 188Re, this radiopharmaceutical should become available for use in many regions of our country. Therefore, there is a need for a comparative analysis of the characteristics of these radiopharmaceuticals, including on the basis of pharmacokinetic modeling.

Purpose of work – to develop a software package for pharmacokinetic modeling and calculation of individual absorbed doses in radionuclide therapy of bone metastases based on a four-compartment kinetics model and to test it on clinical data with various Russian radiopharmaceuticals.

The work is based on the principles and methods of pharmacokinetics of radiopharmaceuticals (compartment modeling). Identification of model parameters (transport constants) was carried out on the basis of urine radiometry data from five patients with a radiopharmaceutical injected into the body. The Hook-Jeeves method was used to find the minimum of the residual functional during identification. The absorbed doses were calculated using the functions of the radiopharmaceutical activity found in the compartments during the simulation.

A complex of modeling and calculation of pharmacokinetic and dosimetric characteristics of osteotropic radiopharmaceuticals based on a four-compartment model of their transport in the human body during radionuclide therapy of bone metastases has been developed. The transport constants of the model were identified for five patients and the individual characteristics of Russian radiopharmaceuticals labeled 89Sr, 153Sm and 188Re were calculated (effective half-lives, maximum activity in the compartments and the time of their achievement, absorbed doses to bone tissue and metastases, endosteal bone layer, red bone marrow, blood, kidneys and bladder). The time activity dependencies for all compartments of the model are obtained and analyzed. A comparative analysis of the pharmacokinetics and dosimetry of three radiopharmaceuticals (89Sr-chloride, 153Sm-oxabiphore, 188Re-solerene) was carried out.

From a comparative analysis of the pharmacokinetic and dosimetric characteristics of the three radiopharmaceuticals, it follows that the best of them for widespread use in many regions of our country should be 188Re-solerene, taking into account the generator method of obtaining 188Re in a hospital.

Matveev A.V. Pharmacokinetics and dosimetry of Russian osteotropic radiopharmaceuticals: modeling and comparative analysis. Biomedicine Radioengineering. 2022. V. 25. № 1. Р. 40-52. DOI: https://doi.org/10.18127/j15604136-202201-05 (In Russian).

1. Murray I., Du Y. Systemic Radiotherapy of Bone Metastases With Radionuclides. Clinical Oncology. 2021. V. 33. P. 98–105. DOI: 10.1016/j.clon.2020.11.028
2. Handkiewicz-Junak D., Poeppel T.D., Bodei L., Aktolun C., Ezziddin S., Giammarile F., Delgado-Bolton R.C., Gabriel M. EANM guidelines for radionuclide therapy of bone metastases with beta-emitting radionuclides. European Journal of Nuclear Medicine and Molecular Imaging. 2018. V. 45. P. 846–859. DOI: 10.1007/s00259-018-3947-x
3. Krylov V.V., Drozdovskiy B.Ya., Tsyb A.F. Radionuklidnaya terapiya v palliativnom lechenii bolnykh s metastazami v ko-sti. Palliativnaya meditsina i reabilitatsiya. 2005. № 3. S. 45–53. (in Russian).
4. Dzhuzha D.A., Sagan D.L. Palliativnaya radionuklidnaya terapiya kostnykh metastazov. Promeneva dіagnostika. promeneva terapіya. 2010. № 1. S. 65–69. (in Russian).
5. Beiki D., Haddad P., Fallahi B., Keyvan A., Gholamrezanezhad A., Mirzaei H., Saghari M., Amouzegar-Hashemi F., Kazemian A., Fard-Esfahani A., Eftekhari M. Effectiveness and complications of 153Sm-EDTMP in palliative treatment of diffuse skeletal metastases. Iranian Journal of Nuclear Medicine. 2013. V. 21. № 1. P. 26–32.
6. Pacilio M., Ventroni G., Basile C., Ialongo P., Becci D., Mango L. Improving the dose-myelotoxicity correlation in radiometabolic therapy of bone metastases with 153Sm-EDTMP. European Journal of Nuclear Medicine and Molecular Imaging. 2014. V. 41. № 2. P. 238–252. DOI: 10.1007/s00259-013-2552-2
7. Zyryanov S.K., Zatolochina K.E. Perspektivy primeneniya radionuklidnykh lekarstvennykh preparatov pri lechenii zlokachestvennykh novoobrazovaniy v RF. Kachestvennaya klinicheskaya praktika. 2018. № 2. S. 51–57. DOI: 10.24411/2588-0519-2018-10044 (in Russian).
8. Liyepe K., Limuris G., Krylov V.V., Kochetova T.Yu. Radionuklidnaya terapiya preparatami 188Re v onkologii. Onkologicheskiy zhurnal: luchevaya diagnostika. luchevaya terapiya. 2018. T. 1. № 4. S.34–42. DOI: 10.37174/2587-7593-2018-1-4-34-42 (in Russian).
9. Petriyev V.M., Afanasyeva E.L., Skvortsov V.G. Osteotropnyye radiofarmpreparaty na osnove fosfonovykh kislot dlya lecheniya kostnykh metastazov cheloveka (obzor). Khimiko-farmatsevticheskiy zhurnal. 2008. T. 42. № 5. S. 3–10 (in Russian).
10. Stepanenko V.F., Yaskova E.K., Belukha I.G., Petriyev V.M., Skvortsov V.G., Kolyzhenkov T.V., Petukhov A.D., Dubov D.V. Raschety doz vnutrennego oblucheniya nano-. mikro- i makro-biostruktur elektronami. beta-chastitsami i kvantovym izlucheniyem razlichnoy energii pri razrabotkakh i issledovaniyakh novykh RFP v yadernoy meditsine. Radiatsiya i risk. 2015. T. 24. № 1. S. 35–60 (in Russian).
11. Tishchenko V.K., Petriyev V.M., Smoryzanova O.A., Mikhaylovskaya A.A. Vliyaniye khimicheskoy struktury fosfonovykh kislot. mechennykh Re-188. na ikh povedeniye v organizme laboratornykh zhivotnykh. Radiatsiya i risk. 2017. T. 26. № 1. S.78–88. DOI: 10.21870/0131-3878-2017-26-1-78-88 (in Russian).
12. Sergiyenko V.I., Dzhelliff R., Bondareva I.B. Prikladnaya farmakokinetika: osnovnyye polozheniya i klinicheskoye pri-meneniye. M.: Izd-vo RAMN. 2003. 208 s. (in Russian).
13. Bellman R. Matematicheskiye metody v meditsine. per. s angl. A.P. Asachenkova. N.A. Shalnovoy; pod red. L.N. Belykh. M.: Mir. 1987. 200 s. (in Russian).
14. Kotina E.D. Programmnyy kompleks «Diagnostika» dlya obrabotki radionuklidnykh issledovaniy. Vestnik Sankt-Peterburgskogo universiteta. 2010. № 2. S. 100–113 (in Russian).
15. Matveyev A.V. Modelirovaniye kinetiki radiofarmpreparatov s izotopami yoda v zadachakh yadernoy meditsiny. Kompyu-ternyye issledovaniya i modelirovaniye. 2020. T. 12. № 4. S. 883–905. DOI: 10.20537/2076-7633-2020-12-4-883-905 (in Russian).
16. Matveyev A.V., Korneyeva M.Yu. Model kinetiki osteotropnogo radiofarmpreparata i opredeleniye pogloshchennykh doz pri radionuklidnoy terapii kostnykh metastazov. Vestnik Omskogo universiteta. 2018. T. 23. № 1. S. 35–42. DOI: 10.25513/1812-3996.2018.23(1).35-42 (in Russian).
17. Dolya O.P., Matusevich E.S., Klepov A.N., Kurachenko Yu.A. Dozimetricheskoye obespecheniye radionuklidnoy diagnostiki i terapii kostnykh metastazov. Almanakh klinicheskoy meditsiny. 2008. T. 17. S. 310–313. (in Russian).
18. Galanin M.P., Khodzhayeva S.R. Razrabotka i testirovaniye metodov resheniya zhestkikh obyknovennykh differentsialnykh uravneniy. Matematicheskoye modelirovaniye i chislennyye metody. 2014. № 4. S. 95–119. (in Russian).
19. Matveyev A.V. Osobennosti rascheta individualnykh farmakokineticheskikh i dozimetricheskikh kharakteristik radiofarm-preparatov u bolnykh s metastazami v kosti pri provedenii radionuklidnoy terapii. Innovatsionnoye razvitiye nauki: fundamentalnyye i prikladnyye problemy: monografiya. Agisheva L.V. i dr. Petrozavodsk: MTsNP «Novaya nauka». 2021. S. 49–72. DOI: 10.46916/18052021-1-978-5-00174-233-3 (in Russian).
20. Matveyev A.V., Korneyeva M.Yu. Farmakokineticheskoye modelirovaniye i raschet pogloshchennykh doz pri radionuklidnoy terapii kostnykh metastazov. Svidetelstvo o gosudarstvennoy registratsii programmy dlya EVM RU 2018616431. 01.06.2018. Zayavka № 2018613961 ot 19.04.2018. (in Russian).
21. Dolya O.P., Klepov A.N., Krylov V.V., Drozdovskiy B.Ya., Matusevich E.S. Dinamika nakopleniya i vyvedeniya 153Sm-oksabifora u bolnykh s metastazami v kosti pri provedenii radionuklidnoy terapii. Radiatsiya i risk. 2007. T. 16.№ 2–4. S. 39–47 (in Russian).
22. Dolya O.P., Matusevich E.S., Klepov A.N. Matematicheskoye modelirovaniye kinetiki transporta osteotropnogo radio-farmpreparata v organizme patsiyentov s metastazami v kosti. Meditsinskaya fizika. 2007. № 2. S. 40–50. (in Russian).
23. Predely postupleniya radionuklidov dlya rabotayushchikh s ioniziruyushchim izlucheniyem. Publikatsiya 30 MKRZ. M.: Energo-atomizdat. 1982. (in Russian).