A Comparative Parallel Study of Pharmacokinetics and Immunogenicity Following Single Intravenous Administration of Bevacizumab Biosimilar RPH-001 (Manufactured by R-Pharm Group, Russia) and Avastin® (Manufactured by F. Hoffmann-La Roche Ltd., Switzerland) in Healthy Male Volunteers

Introduction. Bevacizumab is a monoclonal IgG1 antibody that binds to and inhibits the biologic activity of human vascular endothelial growth factor (VEGF). Bevacizumab is used as a targeted monoor combination therapy for different solid tumors. Phase I clinical trial was performed to assess pharmacokinetics (PK) and immunogenicity of bevacizumab drugs. For this study 80 healthy male volunteers were recruited and randomized to either Avastin or RPH-001 group.

Aim. To assess and compare pharmacokinetics and immunogenicity (safety) following single intravenous administration of Avastin® (manufactured by F. Hoffmann-La Roche Ltd., Switzerland) and bevacizumab biosimilar RPH-001 (manufactured by R-Pharm Group, Russia).

Materials and methods. Bevacizumab quantitation and quasi-quantitative anti-bevacizumab antibodies detection in human blood serum were carried out using photometric ELISA. Two different methods were successfully validated.

Results and discussion. Bevacizumab quantitation method was validated for selectivity and specificity, calibration curve, sensitivity, accuracy and precision, minimal required dilution, dilution linearity and stability. The anti-bevacizumab antibodies detection method was validated for cut-point (with normalization factor calculation), selectivity, sensitivity, precision, drug tolerance, dilution linearity, matrix effect (in case of serum hemolysis), and stability. The validated methods were successfully applied to pharmacokinetic and immunogenicity assessment of bevacizumab drugs.

Conclusion. The results of the PK-study showed that test and reference bevacizumab drugs were equivalent. Immunogenicity study did not show any evidence of anti-bevacizumab antibodies in blood serum samples.

1. WHO fact sheet «Cancer». 12.09.2018. Available at: https://www.who.int/news-room/fact-sheets/detail/cancer.

2. Imyanitov E. N General principles of targeted therapy. Practical Oncology. 2010; 11(3): 123–130 (in Russ.).

3. Feoktistova P. S., Zaginayko A. V., Simanovich E. E., Zharkova O. V., Mironova E. B., Karaseva V. V., Khaylenko V. A. Targeted therapy of metastatic colorectal cancer. P. A. Herzen Journal of Oncology. 2013; 2(3): 31–35 (in Russ.).

4. Drug Bank: bevacizumab. Accession Number: DB00112. Available at: https://www.drugbank.ca/drugs/DB00112.

5. State register of medicines. Available at: https://grls.rosminzdrav.ru/CIPermissionMini.aspx?CIStatementGUID=f33b36db-9d61-43bf-aaaf-ab6ff4697ff9&CIPermGUID=A0624183-5D1D-4E5C-9704-CDBF9EB6D3D7(in Russ.).

6. Mironov A. N. (edit.) Guideline on expertise of medicines. Vol. I. – M.: Grif i K. 2013: 328 (in Russ.).

7. Rules for conducting bioequivalence studies of drug products on the territory of EAEU. 2016 (in Russ.).

8. FDA Guidance for Industry Immunogenicity Testing of Therapeutic Protein Products – Developing and Validating Assays for Anti-Drug Antibody Detection. 2019; 1.

9. Shankar G., Devanarayan V., Amaravadi L., Barrett Y. C., Bowsher R., Finco-Kent D., Fiscella M., Gorovits B., Kirschner S., Moxness M., Parish T., Quarmby V., Smith H., Smith W., Zuckerman L. A., Koren E. Recommendations for the validation of immunoassays used for detection of host antibodies against biotechnology products. J Pharm Biomed Anal. 2008; 48(5): 1267–81.

10. Genentech Inc. Avastin® (bevacizumab) prescribing information. 2004 (last update 06. 2019). Available at: https://www.gene.com/download/pdf/avastin_prescribing.pdf.