Intravenous and oral NOAEL doses of the new PrC-210 aminothiol in swine and dose equivalency in humans to enable clinical trials

• An IV or oral PrC-210 bolus dose yielded easily measurable plasma concentrations, which returned to baseline within an hour (IV) or 8–10 h (oral) • At the same IV mg/kg dose, female pig plasma PrC-210 AUC levels were 13–15% higher than males; this presumably reflects less vasculature per unit tissue mass. • A primary toxicity, vomiting, followed simple PrC-210 plasma toxicokinetics for both IV and oral doses, and was absent at IV PrC-210 NOAEL (5.0 mg/kg bw) and oral PrC-210 NOAEL (70.0 mg/kg bw) doses that are at least two-fold higher than the highest PrC-210 dose that would be administered therapeutically. • No significant changes in blood cell populations were seen through 7 days following an IV PrC-210 bolus NOAEL dose. • No significant changes in any of 15 blood chemistry parameters were seen through 7 days following an IV PrC-210 NOAEL dose. • No discernible visible nor histologic organ or tissue pathology was seen in necropsies performed at 7 days post-IV dose. Reactive Oxygen Species (ROS)-induced cell and organ toxicity is a common element in human disease patho-mechanisms. PrC-210 is a new free-radical scavenger that substantially suppresses ROS damage in pre-clinical animal disease models. Here we determined PrC-210 pharmacokinetic and toxicokinetic performance in a large animal pig model as a forestep to Phase 1 safety studies in humans. Using a newly created LC-MS assay to measure plasma PrC-210 levels, we determined that: i) an IV or oral PrC-210 bolus dose yielded easily measurable plasma concentrations, which returned to baseline within an hour (IV) or 8–10 h (oral), ii) at the same IV mg/kg dose, female pig plasma PrC-210 AUC levels were 13–15 % higher than males; this presumably reflects less vasculature per unit tissue mass, iii) a primary toxicity, vomiting, followed simple PrC-210 plasma toxicokinetics for both IV and oral doses, and was absent at IV PrC-210 NOAEL (5.0 mg/kg bw) and oral PrC-210 NOAEL (70.0 mg/kg bw) doses that are at least two-fold higher than the highest PrC-210 dose that would be administered therapeutically, iv) no significant changes in blood cell populations were seen through 7 days following an IV PrC-210 bolus NOAEL dose, v) no significant changes in any of 15 blood chemistry parameters were seen through 7 days following an IV PrC-210 NOAEL dose, and vi) no discernible visible nor histologic organ or tissue pathology was seen in necropsies performed at 7 days post-IV dose. This study supports continued development of PrC-210 for Phase 1 human studies.