Abstract
TS-DP2 is a recombinant human granulocyte colony stimulating factor (rhG-CSF) manufactured by TS Corporation. We conducted a four-week study of TS-DP2 (test article) in repeated intravenous doses in male and female Sprague-Dawley (SD) rats. Lenograstim was used as a reference article and was administered intravenously at a dose of 1000 µg/kg/day. Rats received TS-DP2 intravenously at doses of 250, 500, and 1000 µg/kg/day once daily for 4 weeks, and evaluated following a 2-week recovery period. Edema in the hind limbs and loss of mean body weight and body weight gain were observed in both the highest dose group of TS-DP2 and the lenograstim group in male rats. Fibro-osseous lesions were observed in the lenograstim group in both sexes, and at all groups of TS-DP2 in males, and at doses of TS-DP2 500 µg/kg/ day and higher in females. The lesion was considered a toxicological change. Therefore, bone is the primary toxicological target of TS-DP2. The lowest observed adverse effect level (LOAEL) in males was 250 µg/kg/day, and no observed adverse effect level (NOAEL) in females was 250 µg/kg/day in this study. In the toxicokinetic study, the serum concentrations of G-CSF were maintained until 8 hr after administration. The systemic exposures (AUC0−24h and C0) were not markedly different between male and female rats, between the administration periods, or between TS-DP2 and lenograstim. In conclusion, TS-DP2 shows toxicological similarity to lenograstim over 4-weeks of repeated doses in rats.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
References
Glaspy, J.A. (2003) Hematopoietic management in oncology practice. Part 1. Myeloid growth factors. Oncology, 17, 1593–1603.
El Ouriaghli, F., Fujiwara, H., Melenhorst, J.J., Sconocchia, G., Hensel, N. and Barrett, A.J. (2003) Neutrophil elastase enzymatically antagonizes the in vitro action of G-CSF: implications for the regulation of granulopoiesis. Blood, 101, 1752–1758.
Yong, K.L. (1996) Granulocyte colony-stimulating factor (GCSF) increases neutrophil migration across vascular endothelium independent of an effect on adhesion: Comparison with granulocyte-macrophage colony-stimulating factor (GMCSF). Br. J. Haematol., 94, 40–47.
Morstyn, G., Campbell, L., Souza, L.M., Alton, N.K., Keech, J., Green, M., Sheridan, W., Metcalf, D. and Fox, R. (1988) Effect of granulocyte colony stimulating factor on neutropenia induced by cytotoxic chemotherapy. Lancet, 1, 667–672.
Price, T.H., Chatta, G.S. and Dale, D.C. (1996) Effect of recombinant granulocyte colony-stimulating factor on neutrophil kinetics in normal young and elderly humans. Blood, 88, 335–340.
Glaspy, J.A., Baldwin, G.C., Robertson, P.A., Souza, L., Vincent, M., Ambersley, J. and Golde, D.W. (1988) Therapy for neutropenia in hairy cell leukemia with recombinant human granulocyte colony-stimulating factor. Ann. Intern. Med., 109, 789–795.
Yokose, N., Ogata, K., Tamura, H., An, E., Nakamura, K., Kamikubo, K., Kudoh, S., Dan, K. and Nomura, T. (1998) Pulmonary toxicity after granulocyte colonystimulating factor-combined chemotherapy for non-Hodgkin’s lymphoma. Br. J. Cancer, 77, 2286–2290.
Johnston, E., Crawford, J., Blackwell, S., Bjurstrom, T., Lockbaum, P., Roskos, L., Yang, B.B., Gardner, S., Miller-Messana, M.A., Shoemaker, D., Garst, J. and Schwab, G. (2000) Randomized, dose-escalation study of SD/ 01 compared with daily filgrastim in patients receiving chemotherapy. J. Clin. Oncol., 18, 2522–2528.
Inazawa, T. (2014) A case of platelet and white blood cell reduction associated with pioglitazone and fenofibrate. Diabetol. Int., 5, 202–205.
Thoolen, B., Maronpot, R.R., Harada, T., Nyska, A., Rousseaux, C., Nolte, T., Malarkey, D.E., Kaufmann, W., Küttler, K., Deschl, U., Nakae, D., Gregson, R., Vinlove, M.P., Brix, A.E., Singh, B., Belpoggi, F. and Ward, J.M. (2010) Proliferative and nonproliferative lesions of the rat and mouse hepatobiliary system. Toxicol. Pathol., 38, 5S–81S.
Welte, K. (2014) G-CSF: filgrastim, lenograstim and biological similars. Expert Opin. Biol. Ther., 14, 983–993.
Akizuki, S., Mizorogi, F., Inoue, T., Sudo, K. and Ohnishi, A. (2000) Pharmacokinetics and adverse events following 5-day repeated administration of lenograstim, a recombinant human granulocyte colony-stimulating factor, in healthy subjects. Bone Marrow Transplant., 26, 939–946.
Stewart, C.A. (1974) Leucocyte alkaline phosphatase in myeloid maturation. Pathology, 6, 287–293.
Izumi, M., Ishikawa, J., Takeshita, A. and Maekawa, M. (2005) Increased serum alkaline phosphatase activity originating from neutrophilic leukocytes. Clin. Chem., 51, 1751–1752.
Frazier, K.S., Seely, J.C., Hard, G.C., Betton, G., Burnett, R., Nakatsuji, S., Nishikawa, A., Durchfeld-Meyer, B. and Bube, A. (2012) Proliferative and nonproliferative lesions of the rat and mouse urinary system. Toxicol. Pathol., 40, 14S–86S.
Kaufmann, W., Bolon, B., Bradley, A., Butt, M., Czasch, S., Garman, R.H., George, C., Gröters, S., Krinke, G., Little, P., McKay, J., Narama, I., Rao, D., Shibutani, M. and Sills, R. (2012) Proliferative and nonproliferative lesions of the rat and mouse central and peripheral systems. Toxicol. Pathol., 40, 87S–157S.
Haschek, W.M., Rousseaux, C.G. and Wallig, M.A. (2010) Fundamentals of toxicologic pathology (2nd edition), Academic Press, San Diego, pp. 1–691.
Peter, M. (2012) Background lesions in laboratory animals: a color atlas. Elsevier, New York, pp. 1–256.
Hard, G.C. and Khan, K.N. (2004) A contemporary overview of chronic progressive nephropathy in the laboratory rat, and its significance for human risk assessment. Toxicol. Pathol., 32, 171–180.
Author information
Authors and Affiliations
Corresponding author
Additional information
This is an Open-Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Rights and permissions
This is an Open-Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://doi.org/creativecommons.org/licenses/by/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
About this article
Cite this article
Lee, J., Lee, K., Choe, K. et al. Four-Week Repeated Intravenous Dose Toxicity and Toxicokinetic Study of TS-DP2, a Novel Human Granulocyte Colony Stimulating Factor in Rats. Toxicol Res. 31, 371–392 (2015). https://doi.org/10.5487/TR.2015.31.4.371
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.5487/TR.2015.31.4.371