This same type of toxicity was observed in the rabbit IV infusions, in which the 5 minute LY2109761 TGF-beta inhibitor infusion of 60 mg/kg was the maximum-tolerated dose. At the end of the infusion of the dose, lethargy, labored breathing and narcosis were observed. All animals appeared to fully recover within 30�C60 minutes after the end of the infusion, again, coincident with the rapidly Axitinib decreasing plasma ST-246 concentrations. Oral administration had not elicited any dose limiting toxicity at 100 mg/kg in rabbits. In NHP, mild ataxia was observed in three out of four animals at the end of the infusion of the 30 mg/kg dose, but in none of the other doses or dosing regimens. In fact, ST-246 had been administered orally daily at 300 mg/kg for as long as three months and had been welltolerated at that dose. As was observed in mice and rabbits, the clinical signs were observed only at the end of the infusion of the highest dose. In NHP this was at the 30 mg/kg dose administered over 4 hours, coincident with the peak plasma concentrations, and resolved after a short period of time. Taken together, the observations of clinical signs at peak plasma concentrations in mice, rabbits, and cynomolgus monkeys after IV infusions of the highest dose level over the shortest time period and resolution of these toxicities coincident with the decrease in plasma concentrations strongly indicate that this observed toxicity was related to the high peak plasma concentrations. Further, the toxicity appears to be reversible, and was not observed when the plasma concentrations were kept at lower concentrations by slower infusion of equivalent doses of ST-246. Although the mechanism of this toxicity is not yet known, the same ataxia was previously observed after oral administration of doses in NHP, where the mean Cmax was approximately 20 mg/mL, similar to that observed after the 4-hour IV infusion of ST-246. This CNS toxicity was also observed at lower doses in the dog, where the maximum-tolerated dose for repeat dose administration for ST-246 was 30 mg/kg. A comparison of the ST-246 concentrations in the CSF and brain between NHP and dogs after comparable doses showed that the concentrations were much higher in the dogs, possibly explaining the unique sensitivity. In each of the species where this toxicity was observed, further investigations demonstrated that slower infusions eliminated the clinical observations, indicating that IV infusions in humans can be conducted safely by initiating any studies with low doses administered as slow IV infusions.