Granulocyte colony stimulating factor: animal studies for risk assessment

In mice, rats, hamsters, dogs, and monkeys, doses of > or = 1.1 microgram/kg/day of r-metHuG-CSF stimulated neutrophil production in bone marrow. There was a resulting rapid release of mature neutrophils from the marrow storage pool into circulation and a distinct neutrophilia maintained for the dosing period in each study. R-metHuG-CSF corrected cyclic hemopoiesis in dogs, established sustained endogenous recovery after lethal bone marrow suppression, and elicited differention and maturation induction and enhanced functional activity of mature neutrophils. Reversible side effects due to an exaggerated pharmacological activity of the growth factor were observed at doses of > or = 115 micrograms/kg/day, with the exception of a rodent-specific osteopathy, which occurred in some animals after 3 months at > or = 5.7 micrograms/kg/day. The only irreversible adverse effect was seen in monkeys at doses of 1150 micrograms/kg/day (equivalent to 200 times the recommended human dose) when leukocyte counts exceeded 100 x 10(9)/liter. It consisted of hyperleukocytosis, leukostasis in terminal capillaries of the brain, followed by tissue hypoxia and intracerebral hemorrhage. Local tolerance of r-metHuG-CSF was good and no hypersensitivity reactions were observed. Antibody formation was minimal in monkeys but occasionally marked in dogs, which is not suprising due to the species difference in the amino acid sequence of the factor. The use of recombinant canine G-CSF, however, did not elicit formation of neutralizing antibodies in dogs. Moreover, relatively few untoward effects were seen in reproductive toxicology except when maternal toxicity or weight loss of dams occurred. In addition, negative results were obtained in all genotoxicity studies performed.