Toxicological Sciences 65, 246-255 (2002)
Copyright © 2002 by the Society of Toxicology
SAFETY EVALUATION |
Twenty-Six-Week Repeat-Dose Toxicity Study of a Recombinant Human Granulocyte Colony-Stimulating Factor Derivative (Nartograstim) in Cynomolgus Monkeys
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* SNBL USA, Ltd., 6605 Merrill Creek Parkway, Everett, Washington 98203;
Shin Nippon Biomedical Laboratories, Ltd., 2438 Miyanoura, Yoshida, Kagoshima 891-1374, Japan; and
Toxicological Research Laboratories, Kyowa Hakko Kogyo Co., Ltd., 2548 Fujimagari, Ube, Yamaguchi 755-8501, Japan
An rhG-CSF derivative, nartograstim (NTG), at dose levels of 0 (saline), 0.1, 1, 10, and 100 µg/kg, was administered subcutaneously to groups of 3 male and 3 female cynomolgus monkeys once daily for 26 weeks to investigate its toxicity. In Week 4 or later, an increase in leukocyte counts consisting mainly of neutrophils was noted in all NTG dose groups, and was considered to be attributable to the pharmacological action of NTG. The degree of this increase was reduced with repetition of dosing. Increases in granulocytic cells and granulocytic cells/erythrocytic cells (G/E) ratio in the bone marrow, increase in serum ALP activity, and enlarged spleens with increase of neutrophils in the red pulp were observed at 10 µg/kg and higher. Anemia was noted at 10 µg/kg and higher in Week 4 and was accompanied by an increase in reticulocytes and a decrease in total cholesterol level at 100 µg/kg. Anti-NTG antibody was detected in 1 female at 100 µg/kg, but neutralizing antibodies were not detected at any dose levels in Week 4. In Weeks 13 and 26, these antibodies were detected sporadically at all dose levels. However, there were considerable individual variations in antibody titer, and no definite correlation could be found between the dose levels and the antibody titer. Seven NTG-dosed animals including 3 high dose-group animals showed obvious increases in leukocyte counts until Week 26 but no obvious elevation of anti-NTG or neutralizing antibody. In these animals, changes including anemia became slighter but were still observed in Week 26. Under the conditions in this study, 1 µg/kg was concluded to be the no-observed-adverse-effect level (NOAEL) in cynomolgus monkeys.
Key Words: rhG-CSF derivative; nartograstim; cynomolgus monkey; granulocytosis; anemia; no observed adverse effect level.
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