Comparative pharmacokinetics of pembrolizumab after single intravenous administration to Macaca fascicularis

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Abstract

Background. Pembrolizumab belongs to a fundamentally new class of antitumor agents with biological source – monoclonal antibodies. when creating generic biological medicinal products, it is necessary to assess the comparability of the pharmacokinetics of the developed drug and the original (reference) drug product in relevant animal species.

Aim. To compare the pharmacokinetics of two drugs with INN pembrolizumab, concentrate for solution for infusion, administered once intravenously to Macaca fascicularis.

Materials and methods. Biosimilar RPH-075 (INN pembrolizumab, JSC R-Pharm, Russia) and reference drug Keytruda® (INN pembrolizumab, MSD International GmbH) were administered once intravenously to male monkeys (2 groups of 4 males each) at a dose of 30 mg/kg. Macaque blood samples were collected for analysis before administration and at 1, 2, 4, 8, 24, 48, 72, 144, 312, 480, 648, 984, 1320 h after administration. Plasma concentrations of the active ingredient were determined by bridging ELISA using commercially available antibodies, followed by calculation of the main pharmacokinetic parameters (Cmax, AUC, MRT, Vss, T1/2, Cl).

Results. Using antibodies more available than commercial reagent kits, the pembrolizumab assay method recommended by the antibody manufacturer has been replicated. The method has been validated and applied to the analysis of biosamples obtained in the preclinical study. There was no effect of the test drug and the reference drug upon single intravenous administration to monkeys condition and animals body weigh; drugs were found to have comparable pharmacokinetic profiles.

Conclusion. The creation of a biosimilar drug in the Russian Federation will improve the treatment of patients with cancer, reduce the cost of treatment and increase the number of patients receiving high-quality medical care.

About the authors

V. M. Kosman

Research-and-manufacturing company “HOME OF PHARMACY”

Author for correspondence.
Email: kosman.vm@doclinika.ru
ORCID iD: 0000-0001-9690-1935

Vera M. Kosman

3/245 Zavodskaya St., Kuzmolovsky urban-type settlement, Vsevolozhsky district, Leningrad region 188663

Russian Federation

M. V. Karlina

Research-and-manufacturing company “HOME OF PHARMACY”

ORCID iD: 0000-0002-6292-8934

Marina V. Karlina

3/245 Zavodskaya St., Kuzmolovsky urban-type settlement, Vsevolozhsky district, Leningrad region 188663

Russian Federation

T. N. Barybina

Research-and-manufacturing company “HOME OF PHARMACY”

ORCID iD: 0000-0002-7428-9092

Tatyana N. Barybina

3/245 Zavodskaya St., Kuzmolovsky urban-type settlement, Vsevolozhsky district, Leningrad region 188663

Russian Federation

N. M. Faustova

Research-and-manufacturing company “HOME OF PHARMACY”

ORCID iD: 0000-0002-6866-5741

Natalia M. Faustova

3/245 Zavodskaya St., Kuzmolovsky urban-type settlement, Vsevolozhsky district, Leningrad region 188663

Russian Federation

A. A. Matichin

Research-and-manufacturing company “HOME OF PHARMACY”

ORCID iD: 0000-0001-7478-4942

Aleksandr A. Matichin

3/245 Zavodskaya St., Kuzmolovsky urban-type settlement, Vsevolozhsky district, Leningrad region 188663

Russian Federation

V. G. Makarov

Research-and-manufacturing company “HOME OF PHARMACY”

ORCID iD: 0000-0002-2447-7888

Valery G. Makarov

3/245 Zavodskaya St., Kuzmolovsky urban-type settlement, Vsevolozhsky district, Leningrad region 188663

Russian Federation

M. N. Makarova

Research-and-manufacturing company “HOME OF PHARMACY”

ORCID iD: 0000-0003-3176-6386

Marina N. Makarova

3/245 Zavodskaya St., Kuzmolovsky urban-type settlement, Vsevolozhsky district, Leningrad region 188663

Russian Federation

A. A. Dmitrieva

Joint-Stock Company “R-Pharm”

ORCID iD: 0000-0003-4743-6189

Anastasia A. Dmitrieva

Bld 1, 19 Berzarin St., Moscow 123154

Russian Federation

E. V. Shipaeva

Joint-Stock Company “R-Pharm”

ORCID iD: 0000-0002-5953-984X

Elena V. Shipaeva

Bld 1, 19 Berzarin St., Moscow 123154

Russian Federation

A. I. Podolyakina

Joint-Stock Company “R-Pharm”

ORCID iD: 0009-0002-5602-7926

Anna I. Podolyakina

Bld 1, 19 Berzarin St., Moscow 123154

Russian Federation

O. V. Filon

Joint-Stock Company “R-Pharm”

ORCID iD: 0000-0002-8735-7429

Olga V. Filon

Bld 1, 19 Berzarin St., Moscow 123154

Russian Federation

M. Yu. Samsonov

Joint-Stock Company “R-Pharm”

ORCID iD: 0000-0003-2685-1623

Mikhail Yu. Samsonov

Bld 1, 19 Berzarin St., Moscow 123154

Russian Federation

V. G. Ignatiev

Joint-Stock Company “R-Pharm”

ORCID iD: 0000-0003-2818-6583

Vasiliy G. Ignatiev

Bld 1, 19 Berzarin St., Moscow 123154

Russian Federation

References

  1. Centanni M., Moes D.J.A.R., Trocóniz I.F. et al. Clinical pharmacokinetics and pharmacodynamics of immune checkpoint inhibitors. Clin Pharmacokinet 2019;58(7):835–57. doi: 10.1007/s40262-019-00748-2
  2. Desnoyer A., Broutin S., Delahousse J. et al. Pharmacokinetic/ pharmacodynamic relationship of therapeutic monoclonal antibodies used in oncology: Part 2, immune checkpoint inhibitor antibodies. Eur J Cancer 2020;128:119–28. doi: 10.1016/j.ejca.2020.01.003
  3. Jaffar-Aghaei M., Khanipour F., Maghsoudi A. et al. QbD-guided pharmaceutical development of Pembrolizumab biosimilar candidate PSG-024 propelled to industry meeting primary requirements of comparability to Keytruda®. Eur J Pharm Sci 2022;173:106171. doi: 10.1016/j.ejps.2022.106171
  4. Ahamadi M., Freshwater T., Prohn M. et al. Model-based characterization of the pharmacokinetics of pembrolizumab: a humanized anti-PD-1 monoclonal antibody in advanced solid tumors. CPT Pharmacometrics Syst Pharmacol 2017;6(1):49–57. doi: 10.1002/psp4.12139
  5. Raedler L.A. Keytruda (pembrolizumab): first PD-1 inhibitor approved for previously treated unresectable or metastatic melanoma. Am Health Drug Benefits. 2015;8(Spec Feature):96–100.
  6. Longoria T.C., Tewari K.S. Evaluation of the pharmacokinetics and metabolism of pembrolizumab in the treatment of melanoma. Expert Opin Drug Metab Toxicol 2016;12(10):1247–53. doi: 10.1080/17425255.2016.1216976
  7. Gutorov S.L., Borisova E.I., Abramov M.E. et al. Non-small cell lung cancer. Expanding therapeutic possibilities: pembrolizumab in a number of malignant tumors. Farmateka = Pharmateca 2017;8(341):71–5. (In Russ.).
  8. Samoilenko I.V., Demidov L.V. Pembrolizumab in the treatment of metastatic melanoma. Meditsinskiy sovet = Medical Council 2017;(6):8–23. (In Russ.). doi: 10.21518/2079-701X-2017-6-8-23
  9. Rumyantsev A.A. Lenvatinib and pembrolizumab in the treatment of metastatic endometrial cancer: literature review and case report. Meditsinskiy sovet = Medical Council 2021;(20):124–28. (In Russ.). doi: 10.21518/2079-701X-2021-20-124-128
  10. Kedrova A.G., Berishvili A.I., Greyan Т.А. Lenvatinib and pembrolizumab in patients with advanced uterine cancer. Opukholi zhenskoy reproduktivnoy sistemy = Tumors of female reproductive system 2020;16(3):72–80. (In Russ.). doi: 10.17650/1994-4098-2020-16-3-72-80
  11. Gafanov R.A., Dzidzaria A.G., Kravtsov I.B., Fastovets S.V. Combination of pembrolizumab and axitinib: a new gold standard in the first-line therapy for metastatic clear-cell renal-cell carcinoma? Onkourologiya = Cancer Urology 2020;16(3):29–37. (In Russ.). doi: 10.17650/1726-9776-2020-16-3-29-37
  12. Ferlay J., Steliarova-Foucher E., Lortet-Tieulent J. et al. Cancer incidence and mortality patterns in Europe: estimates for 40 countries in 2012. Eur J Cancer. 2013;49(6):1374–403. doi: 10.1016/j.ejca.2012.12.027
  13. Seiwert T.Y., Burtness B., Mehra R. et al. Safety and clinical activity of pembrolizumab for treatment of recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-012): an open-label, multicentre, phase 1b trial. Lancet Oncol 2016;17(7):956–65. doi: 10.1016/S1470-2045(16)30066-3
  14. Kuruvilla J., Armand P., Hamadan M. et al. Pembrolizumab for patients with non-Hodgkin lymphoma: phase 1b KEYNOTE-013 study. Leuk Lymphoma 2023;64(1):130–9. doi: 10.1080/10428194.2022.2136956
  15. Suzman D.L., Agrawal S., Ning Y-M et al. FDA approval summary: atezolizumab or pembrolizumab for the treatment of patients with advanced urothelial carcinoma ineligible for cisplatin‐containing chemotherapy. Oncologist 2019;24(4):563–9. doi: 10.1634/theoncologist.2018-0084
  16. Diaz L.A. Jr, Shiu K.K., Kim T.W. et al. Pembrolizumab versus chemotherapy for microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer (KEYNOTE-177): final analysis of a randomised, open-label, phase 3 study. Lancet Oncol 2022;23(5):659–70. doi: 10.1016/S1470-2045(22)00197-8
  17. Protasova A.E., Strakh L.V., Lando E.I., Sidorkina E.V. Metastatic cervical cancer: clinical experience with pembrolizumab application. Case report. Sovremennaya onkologiya = Journal of Modern Oncology 2021;23(2):340–4. (In Russ.). doi: 10.26442/18151434.2021.2.201009
  18. Bachu R.D., Abou-Dahech M., Balaji S. et al. Oncology biosimilars: New developments and future directions. Cancer Rep (Hoboken) 2022;5(11):e1720. doi: 10.1002/cnr2.1720
  19. Fedyanin M.Yu., Snegovoy A.V., Breder V.V. et al. Toxicity associated with immune checkpoint inhibitors: analysis of immune-related adverse events with a pembrolizumab biosimilar (Pembroria). Bezopasnost y risk farmakoterapii = Safety and Risk of Pharmacotherapy 2023;11(2):215–30. doi: 10.30895/2312-7821-2023-11-2-360
  20. Shestakova M.V., Vikulova O.K. Biosimilars: presumption of guilt. Sakharniy diabet = Diabetes mellitus 2011;14(4):91–9. (In Russ.). doi: 10.14341/2072-0351-5825
  21. Eltsova E.A., Ramenskaya G.V., Smolyarchuk E.A., Bushmanova A.V. Biosimilars – drugs of the future. Farmakokinetika i Farmakodinamika = Pharmacokinetics and Pharmacodynamics 2015;(1):12–5. (In Russ.).
  22. Watanabe T., Kiso M., Fukuyama S. at al. Characterization of H7N9 influenza A viruses isolated from humans. Nature 2013;501(7468):551–5. doi: 10.1038/nature12392
  23. Hobson W. Safety assessment studies in nonhuman primates. Int J Toxicol 2000;19(2):141–7. doi: 10.1080/109158100224962
  24. Zhang Y., Huo M., Zhou J., Xie S. PKSolver: An add-in program for pharmacokinetic and pharmacodynamic data analysis in Microsoft Excel. Comput Methods Programs Biomed 2010;99(3):306–14. doi: 10.1016/j.cmpb.2010.01.007
  25. Dolgov V.V., Morozova V.T., Marcishevskaya R.L. Clinical and diagnostic value of laboratory parameters. Moscow: Centr, 1995. 214 p. (In Russ.).
  26. Kuksova M.I. The hematopoietic system of monkeys is normal and pathological. Moscow: Medicina, 1972. 128 p. (In Russ.).
  27. Lapin B.A., Dzhikidze E.K., Krylova R.I. et al. Problems of infectious pathology of monkeys. Moscow: Izd-vo RAMN, 2004. 140 p. (In Russ.).
  28. Лапин Б.А., Джикидзе Э.К., Фридман Э.П. Руководство по медицинской приматологии. М.: Медицина, 1987. 192 с. Lapin B.A., Dzhikidze E.K., Fridman E.P. A guide to medical primatology. Moscow: Medicina, 1987. 192 р. (In Russ.).
  29. Wang H.W., Ying N., Wei S. et al. Reference data of clinical chemistry, haematology and blood coagulation parameters in juvenile cynomolgus monkeys (Macaca fascicularis). Vet Med 2018;57(5):233–8. doi: 10.17221/5953-VETMED
  30. Fu J., Wang F., Dong L.H. et al. Preclinical evaluation of the efficacy, pharmacokinetics and immunogenicity of JS-001, a programmed cell death protein-1 (PD-1) monoclonal antibody. Acta Pharmacol Sin 2017;38(5):710–8. doi: 10.1038/aps.2016.161
  31. Lopes J.E., Sun L., Flick H.L. et al. Pharmacokinetics and pharmacodynamic effects of nemvaleukin alfa, a selective agonist of the intermediate-affinity IL-2 receptor, in cynomolgus monkeys. J Pharmacol Exp Ther 2021;379(2):203–10. doi: 10.1124/jpet.121.000612
  32. Hutchins B., Starling G.C., McCoy M.A. et al. Biophysical and immunological characterization and in vivo pharmacokinetics and toxicology in nonhuman primates of the anti-PD-1 antibody pembrolizumab. Mol Cancer Ther 2020;19(6):1298–307. doi: 10.1158/1535-7163

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