Pharmacokinetics of pertuzumab biosimilar compared with the original drug in cynomolgus monkeys

Abstract

BACKGROUND: Developing biosimilar monoclonal antibodies for treating malignant diseases is a critical task. RPH-051 (pertuzumab) is a biosimilar drug, a recombinant humanized monoclonal antibody targeting type 2 human epidermal growth factor receptors. At the stage of non-clinical development, studies of pharmacokinetics of biosimilar vs. original drug product in a relevant animal species, provide important information on the comparability of drugs.

AIM: To evaluate the pharmacokinetics of the biosimilar product RPH-051 in comparison with the original drug after a single intravenous injection in a cynomolgus monkey model.

MATERIALS AND METHODS: The study was conducted in 8 cynomolgus monkeys (Macaca fascicularis) divided into 2 groups, each including 2 females and 2 males. The first group received the biosimilar RPH-051 (international nonproprietary name is pertuzumab, AO R-Pharm, Russia), the second group was treated with the comparator Perjeta^® (international nonproprietary name is pertuzumab). The drugs were administered as a single intravenous dose of 50 mg/kg. Blood samples were collected before dosing, then at 1 min, 1, 2, 4, 8, 24 h, and on days 3, 7, 10, 14, 21 and 28 post-dosing. Quantitative analysis of pertuzumab serum levels was performed using enzyme-linked immunosorbent assay (ELISA) with spectrophotometric detection in the visible range of the spectrum.

RESULTS: The method of quantitative assessment of serum level of pertuzumab using (ELISA) in cynomolgus monkeys was developed. The method was validated against the following parameters: selectivity, minimum required dilution, lower limit of quantification, calibration range, accuracy and precision (within the analytical run and between runs), specificity, linearity (possibility) of sample dilution, parallelism, and stability of the analyte in serum.

Comparability of the drugs in the main pharmacokinetic parameters was established. The mean C_max and AUC_last values of RPH-051 and of the comparator were 1684.34 and 1405.34 μg/mL (C_max); 265,282.18 and 280,168.92 (μg/mL)×h (AUC_last), respectively.

CONCLUSION: Comparability between the pharmacokinetic profiles of the biosimilar RPH-051 and the originator’s drug was demonstrated. In the course of the study, no adverse clinical events, animal body weight changes, or injection site reactions associated with the tested drugs were observed.

Keywords

pertuzumab / biosimilar / pharmacokinetics / blood serum / enzyme-linked immunoassay / cynomolgus monkey

References

[1] New Russian biosimilars and generics against cancer occupied 60% of the entire clinical research market in Russia. Scientific and Production Journal of Drug Development and Registration [Internet]. [cited 2024 Sep 17]. Available from: https://www.pharmjournal.ru/jour/announcement/view/1442.

[2] Новые российские биоаналоги и дженерики против рака заняли 60% всего рынка клинических исследований в России // Научно-производственный журнал разработка и регистрация лекарственных средств. Режим доступа: https://www.pharmjournal.ru/jour/announcement/view/1442. Дата обращения: 17.09.2024.

[3] Giri M, Giri M, Thapa RJ, et al. Breast Cancer in Nepal: Current Status and Future Directions. Biomedical Reports. 2018; 8(4);325–329.

[4] Giri M., Giri M., Thapa R., et al. Breast Cancer in Nepal: Current Status and Future Directions // Biome Rep. 2018. Vol. 8, N 4. P. 325–329. doi: 10.3892/br.2018.1057

[5] Trapani D, Ginsburg O, Fadelu T. et al. Global challenges and policy solutions in breast cancer control. Cancer Treatment Reviews. 2022; 104

[6] Trapani D., Ginsburg O., Fadelu T., et al. Global challenges and policy solutions in breast cancer control // Cancer Treat Rev. 2022. Vol. 104. P. 102339. doi: 10.1016/j.ctrv.2022.102339

[7] Frolova MA. Neoadjuvant systemic therapy of HER2-positive breast cancer. Journal of Modern Oncology. 2015;17(4):22–25.

[8] Фролова М.А. Неоадъювантная лекарственная терапия при HER2-позитивном раке молочной железы // Современная Онкология. 2015. Т. 17, № 4. С. 22–25.

[9] Cross-Discipline team leader review; Center for Drug Evaluation and Research [Internet]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/125409Orig1s000CrossR.pdf

[10] Cross-Discipline team leader review; Center for Drug Evaluation and Research [Internet]. Режим доступа: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/125409Orig1s000CrossR.pdf Дата обращения: 22.07.2024.

[11] Volskaya E. Biosimilars: regulations specificity. Remedium. 2011;3:10–12. Available from: https://cyberleninka.ru/article/n/biosimilyary-osobennosti-regulyatornyh-norm

[12] Вольская Е. Биосимиляры: особенности регуляторных норм // Ремедиум. 2011. № 3. С. 10–12. Режим доступа: https://cyberleninka.ru/article/n/biosimilyary-osobennosti-regulyatornyh-norm. Дата обращения: 23.07.2024.

[13] Eltcova EA, Ramenskaya GV, Smolyarchuk EA, Bushmanova AV. Biosimilars — drugs of the future. Pharmacokinetics and Pharmacodynamics. 2015;(1):12–15. EDN: UCDSXN

[14] Ельцова Е.А., Раменская Г.В., Смолярчук Е.А., Бушманова А.В. Биосимиляры — препараты будущего // Фармакокинетика и Фармакодинамика. 2015. Т. 1. С. 12–15. EDN: UCDSXN

[15] Niyazov RR, Dranitsyna MA, Vasiliev AN, Gavrishina EV. Biosimilars: development and investigation using achievements in modern biotechnology. Diabetes mellitus. 2020;23(6):548–560. EDN: MSIKHJ doi: 10.14341/DM12576

[16] Ниязов Р.Р., Драницына М.А., Васильев А.Н., Гавришина Е.В. Биоаналоги: разработка и изучение с помощью современных биотехнологий // Сахарный диабет. 2020. № 6. С. 548–560. EDN: MSIKHJ doi: 10.14341/DM12576

[17] Ishii-Watabe A, Kuwabara T. Biosimilarity assessment of biosimilar therapeutic monoclonal antibodies. Drug Metabolism and Pharmacokinetics. 2019;34(1):64–70. doi: 10.1016/j.dmpk.2018.11.004

[18] Ishii-Watabe A., Kuwabara T. Biosimilarity assessment of biosimilar therapeutic monoclonal antibodies // Drug Metab Pharmacokinet. 2019. Vol. 34, N 1. P. 64–70. doi: 10.1016/j.dmpk.2018.11.004

[19] Kwon O, Joung J, Park Y, et al. Considerations of critical quality attributes in the analytical comparability assessment of biosimilar products. Biologicals. 2017;48:101–108. doi: 10.1016/j.biologicals.2017.04.005

[20] Kwon O., Joung J., Park Y., et al. Considerations of critical quality attributes in the analytical comparability assessment of biosimilar products // Biologicals. 2017. Vol. 48, P. 101–108. doi: 10.1016/j.biologicals.2017.04.005

[21] Al-Sabbagh A, Olech E, McClellan JE, Kirchhoff CF. Development of biosimilars. Seminars in Arthritis Rheumatism. 2016;45(5):11–18.

[22] Al-Sabbagh A., Olech E., McClellan J., Kirchhoff C. Development of biosimilars // Semin Arthritis Rheum. 2016. Vol. 45, N 5. P. 11–18. doi: 10.1016/j.semarthrit.2016.01.002

[23] Mahmood I, Green MD. Pharmacokinetic and pharmacodynamic considerations in the development of therapeutic proteins. Clinical Pharmacokinetics. 2005;44(4):331–347. doi: 10.2165/00003088-200544040-00001

[24] Mahmood I., Green M. Pharmacokinetic and pharmacodynamic considerations in the development of therapeutic proteins // Clin Pharmacokinet. 2005. Vol. 44, N 4. P. 331–347. doi: 10.2165/00003088-200544040-00001

[25] Chapman K, Adjei A, Baldrick P, et al. Waiving in vivo studies for monoclonal antibody biosimilar development: National and global challenges. MAbs. 2016;8(3):427–435. doi: 10.1080/19420862.2016.1145331

[26] Chapman K., Adjei A., Baldrick P., et al. Waiving in vivo studies for monoclonal antibody biosimilar development: National and global challenges // MAbs. 2016. Vol. 8, N 3. P. 427–435. doi: 10.1080/19420862.2016.1145331

[27] Webster C, Wong A, Woollett G. An Efficient Development Paradigm for Biosimilars. BioDrugs. 2019;33(6):603–611. doi: 10.1007/s40259-019-00371-4

[28] Webster C., Wong A., Woollett G. An Efficient Development Paradigm for Biosimilars // BioDrugs. 2019. Vol. 33, N 6. P. 603–611. doi: 10.1007/s40259-019-00371-4

[29] Van Meer PJ, Kooijman M, Van der Laan JW, et al. The value of non-human primates in the development of monoclonal antibodies. Nature Biotechnology. 2013;31(10):882–883. doi: 10.1038/nbt.2709

[30] Van Meer P., Kooijman M., Van der Laan J., et al. The value of non-human primates in the development of monoclonal antibodies // Nature Biotechnology. 2013. Vol. 31, N 10. P. 882–883. doi: 10.1038/nbt.2709

[31] Van Aerts L, De Smet K, Reichmann G, et al. Biosimilars entering the clinic without animal studies. mAbs. 2014;6(5):1155–1162. doi: 10.4161/mabs.29848

[32] Van Aerts L., De Smet K., Reichmann G., et al. Biosimilars entering the clinic without animal studies // MAbs. 2014. Vol. 6, N 5. P. 1155–1162. doi: 10.4161/mabs.29848

[33] Center for Drug Evaluation and Research. Pharmacology review(s). Perjeta (pertuzumab) [Internet]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/

[34] Center for Drug Evaluation and Research. Pharmacology review(s). Perjeta (pertuzumab) [Internet]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/125409Orig1s000PharmR.pdf

[35] Samsonov MYu, Dmitrieva AA, Konopleva GE, et al. Nonclinical studies of biotechnology derived products – theory and practice specificity. Medical Journal of the Russian Federation. 2018;24(6):324–331. EDN: YYFOWL doi: 10.18821/0869-2106-2018-24-6-324-331

[36] Самсонов М.Ю., Дмитриева А.А., Коноплева Г.Е., и др. Специфика теории и практики доклинических исследований биотехнологических лекарственных средств // Российский медицинский журнал. 2018. Т. 24. № 6. С. 324–331. EDN: YYFOWL doi: 10.18821/0869-2106-2018-24-6-324-331

Funding

АО "Р-Фарм"JSC "R-PHARM"

RIGHTS & PERMISSIONS

Eco-Vector