Study of PEG-Filstim sub-acute toxicity

  • V. L. Karbovskyi LLC Pharmaceutical plant «Biopharma», Bila Tserkva
  • I. A. Shevchuk LLC Pharmaceutical plant «Biopharma», Bila Tserkva
  • O. V. Kurkina LLC Pharmaceutical plant «Biopharma», Bila Tserkva
  • T. Ye. Makovska Main Military Clinical Hospital, Kyiv
Keywords: filgrastim, pegfilgrastim, neutropenia, sub-acute toxicity, PEG-Filstim


Febrile neutropenia caused by cytostatic therapy in the treatment of oncological diseases is a frequent complication, which results in enforced reduction in chemotherapy doses and lower effectiveness of the treatment. Introduction of the recombinant forms of the natural protein granulocyte colony-stimulating factor into clinical practice has allowed to minimize the negative consequences of myelosuppressive therapies. The main task of repeated dose toxicity studies of drugs is evaluation of damaging effects of the pharmacological substance, revealing the most sensitive organs and systems in the body.

Therefore, our work was aimed at studying sub-acute toxicity of PEG-Filstim.

Toxicity study of PEG-Filstim was performed in 50 white wild-type rats of both sexes with body weight 170 to 230 g on daily (28 days) subcutaneous administration in the doses of 0.5, 1.0 and 2.0 mg/kg. During the whole observational period, survival, water and food consumption, body weight and symptoms of intoxication were registered. After completion of the experiment, spontaneous diurnal diuresis was evaluated and clinical blood and urine examination performed in all groups of animals.

The results have shown that PEG-Filstim on daily subcutaneous administration in the doses of 0.5, 1.0 and 2.0 mg/kg during 28 days does not cause death in the animals, nor general toxic effects on health, behaviour, food and water consumption, body weight growth in laboratory rats. Upon repeated administration in the studied doses, PEG-Filstim does not affect protein, lipid, carbohydrate metabolism, does not impair functions of urinary and hepatobiliary systems, but increases blood serum alkaline phosphatase activity. PEG-Filstim causes development of pronounced neutrophil leucocytosis and increase in monocyte, lymphocyte and eosinophil count. In the maximum dose of 2.0 mg/kg the studied drug decreases blood red cell count and haemoglobin level.


1. Bretzel RL Jr., Cameron R., Gustas M. et al. Dose intensity in early stage breast cancer: a community practice experience // J. Oncol. Pract - 2009. - V. 5, N 6. - P. 287-290.
2. Kuderer N., Dale D., Crawford J., Lyman G. Impact of primary prophylaxis with granulocyte colony stimulating factor on febrile neutropenia and mortality in adult cancer patients receiving chemotherapy: a systematic review // J. Clin. Oncol - 2007. - V. 25. - P. 3158-6731.
3. Kubo K., Miyazaki Y., Murayama T. et al. A randomized, double-blind trial of pegfilgrastim versus filgrastim for the management of neutropenia during CHASE (R) chemotherapy for malignant lymphoma // Br. J. Haematol. - 2016. - V. 174 (4). - P. 563-570.
4. Zhou C., Huang Y., Wang D et al. A randomized multicenter phase III study of single administration of mecapegfilgrastim (HHPG-19K), a pegfilgrastim biosimilar, for the prophylaxis of chemotherapy-induced neutropenia in patients with advanced non-small cell lung cancer (NSCLC) // Clin. Lung Cancer - 2016 - V. 17 (2). - P. 119-127.
5. Yang B. B., Kido A. Pharmacokinetics and pharmacodynamics of pegfilgrastim. // clin Pharmacokinetic. - 2011. - V. 50 (5). - P. 295-306.
6. Holmes F. A., Jones S. E., O'Shaughnessy J. et al. Comparable efficacy and safety profiles of once-per-cycle pegfilgrastim and daily injection of filgrastim in hemotherapy-induced neutropenia: a multicenter dose-finding study in women with breast cancer // Ann. Oncol - 2002. - V. 13 (6). - P. 903-909.
7. Order of the Ministry of Health of Ukraine No. 944 of 14.12.2009 "Procedure for Pre-clinical Study of Medicines and Examination of Materials for Preclinical Study of Medicinal Products".
8. Stefanov O., Bukhtiarova T., Kovalenko V. and others. Instruction CT-NMOSU 42-6.0: 2008. Medicines. Good laboratory practice (official publication). - K. Morion, 2009. - P. 37-68.
9. European Convention for the protection of vertebrate animals used for experimental and other scientific purposes: Council of Europe, 18.03.1986. - Strasbourg, 1986. - 52 p.
10. Preclinical research of medicinal products. Method. recommendations / Ed. O. V. Stefanova. - K .: Avicenna, 2001. - 528 p.
11. Product Monograph. Neulasta® (pegfilgrastim). Sterile Solution for Injection (Subcutaneous Use Only) 6 mg (10 mg / mL). - Amgen Canada Inc., Date of Authorization: 21. 06. 2012. - 26 p.
12. Barinov E. F., Kot A. G., Yakubenko E. D., Buryak L. A. Optimization of Conditions for Investigation of Functions of the Kidney in a Chronic Experiment // Phys. journ - 1987. - Vol. 33, No. 6. - P. 80-82.
13. Laboratory research in the clinic, ed. V. Menshikov - Moscow: Medicine, 1987. - 365 p.
14. Rebrova O. Yu. Statistical analysis of medical data. Application of the STATISTICA application package. 3rd ed. - M .: Media Sphere, 2006. - 312 p.
15. The problem of norm in toxicology. (Modern concepts and methodological approaches, basic parameters and constants) / Ed. prof. I.M. Trachtenberg. - Moscow: Medicine, 1991. - 204 c.
How to Cite
Karbovskyi, V. L., Shevchuk, I. A., Kurkina, O. V., & Makovska, T. Y. (2018). Study of PEG-Filstim sub-acute toxicity. Farmatsevtychnyi Zhurnal, (2), 77-86.

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