EXPOSURE-BASED SAFETY EVALUATION OF RECOMBINANT HUMAN MACROPHAGE-COLONY-STIMULATING FACTOR (M-CSF) IN CYNOMOLGUS MONKEYS

The safety of M-CSF was assessed in cynomolgus monkeys in an intraveno us dosing regimen. Exposure (AUC(0-24)) multiples (monkey vs human) we re calculated using the no observable adverse effect level (NOAEL) obs erved in this study and correlated with known M-CSF-induced toxicities in a previous continuous intravenous infusion (civ) study in monkeys, M-CSF was administered by daily intravenous infusion (2 h) to cynomol gus monkeys (2/sex/group) at 0.1, 0.3, 0.7, and 1.0 mg/kg/day, for 28 consecutive days. Control animals (2/sex) received placebo. The 0.7 mg /kg/day group was held for an additional 4-week recovery period, Crite ria evaluated included physical observations, ophthalmoscopy, electroc ardiography, body weight, food consumption, clinical pathology, antibo dy formation, pharmacokinetics, necropsy, organ weights, and histopath ology. The only effect previously seen in monkeys after intravenously administered M-CSF occurred in animals in the 0.7 and 1.0 mg/kg/day gr oups, They exhibited a slight decrease in platelets between days 4 and 12 with subsequent recovery, No effects related to M-CSF administrati on were evident in macroscopic or microscopic evaluations and there wa s no evidence of anti-M-CSF antibody production. M-CSF at all dose lev els was completely eliminated within each dosing interval with no accu mulation. Clearance of M-CSF was enhanced during the first week of dos ing, but returned to baseline clearance levels by day 27, This dosing regimen was shown to be remarkably free of toxicities noted in a previ ous monkey study where M-CSF was given by civ at similar daily doses, At the high dose, which was considered to be the NOAEL, the AUC(0-24) was 40-fold greater than the AUC(0-24) in clinical trials where 2.0 mg /m(2) was administered by a daily 2-h infusion. (C) 1998 Society of To xicology.