Acute toxicology and pharmacokinetic assessment of a ribozyme (ANGIOZYME (TM)) targeting vascular endothelial growth factor receptor mRNA in the cynomolgus monkey

The potential acute toxicity of a ribozyme (ANGIOZYME(TM)) targeting the fl t-1 vascular endothelial growth factor (VEGF) receptor mRNA was evaluated i n cynomolgus monkeys following i.v. infusion or s.c. injection. ANGIOZYME w as administered as a 4-hour i.v. infusion at doses of 10, 30, or 100 mg/kg or a s.c. bolus at 100 mg/kg, End points included blood pressure, electroca rdiogram (ECG), clinical chemistry, hematology, complement factors, coagula tion parameters, and ribozyme plasma concentrations, ANGIOZYME was well tol erated, with no drug-associated morbidity or mortality. There was no clear evidence of ANGIOZYME-related adverse effects in this study, Slight increas es in spleen weight and lymphoid hyperplasia were observed in several anima ls. However, these changes were not dose dependent. Steady-state concentrat ions of ANGIOZYME were achieved during the 4-hour infusion of 10, 30, or 10 0 mg/kg, Dose-dependent elimination of ANGIOZYME was observed, with faster clearance at the two highest doses. ANGIOZYME was slowly absorbed after s.c . administration, resulting in steady-state concentrations for the 9-hour s ampling period. Monkeys in this toxicology study received significant plasm a ANGIOZYME exposure by both the s.c. and i.v. routes.