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 AbMole Oleandrin 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 1000 and 2000 mg/kg doses in NHP, where the mean Cmax was approximately 20 mg/mL, similar to that observed after the 4-hour IV infusion of 30 mg/kg 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. The plasma concentration time curves in rabbits dropped very rapidly after the end of the infusion compared to what had been observed after oral administration, where AbMole Acetrizoic acid apparently prolonged absorption provided a long terminal elimination phase with relatively high concentrations after a single oral administration of 100 mg/kg. Interestingly, as the IV infused dose was increased from 30 to 60 mg/kg, the concentration observed during the terminal elimination phase increased, suggesting that higher doses may have, as was observed in NHP, saturated some mechanism of clearance. The rapid decrease in plasma concentrations in rabbits after the end of the infusions suggests prolonged infusions might be required for efficacy studies in rabbits. Additional infusions studies would be needed to confirm the potential relationship between administered dose and clearance in rabbits. The oral ST-246 study in NHP evaluated the pharmacokinetics over a dose range which encompassed those used in efficacy studies, from 0.3 to 30 mg/kg. The results demonstrated that absorption appeared to be saturated as the orally administered dose was increased, and this was reflected in both the Cmax concentrations as well as the exposure. Although the Cmax as well as the exposure increased over this oral dose range, they increased less than dose-proportionally. The Cmax increased only 37-fold over the 100-fold dose increase, while the exposure, as measured by the AUCinf, increased 84-fold, much closer to the 100-fold dose increase.