Exposure-based safety evaluation of recombinant human macrophage colony-stimulating factor (M-CSF) in cynomolgus...

The safety of M-CSF was assessed in cynomolgus monkeys in an intravenous dosing regimen. Exposure (AUC0-24) multiples (monkey vs human) were calculated using the no observable adverse effect level (NOAEL) observed 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 cynomolgus 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. Criteria evaluated included physical observations, ophthalmoscopy, electrocardiography, body weight, food consumption, clinical pathology, antibody formation, pharmacokinetics, necropsy, organ weights, and histopathology. 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 groups. They exhibited a slight decrease in platelets between days 4 and 12 with subsequent recovery. No effects related to M-CSF administration were evident in macroscopic or microscopic evaluations and there was no evidence of anti-M-CSF antibody production. M-CSF at all dose levels was completely eliminated within each dosing interval with no accumulation. Clearance of M-CSF was enhanced during the first week of dosing, but returned to baseline clearance levels by day 27. This dosing regimen was shown to be remarkably free of toxicities noted in a previous 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 AUC0-24 was 40-fold greater than the AUC0-24 in clinical trials where 2.0 mg/m2 was administered by a daily 2-h infusion.