Pharmacokinetics and Tolerability of an Antiangiogenic Ribozyme (ANGIOZYME™) in Healthy Volunteers

The pharmacokinetics and tolerability of a chemically stabilized synthetic ribozyme (ANGIOZYME™) targeting the Flt‐1 VEGF receptor mRNA were evaluated in healthy volunteers. In a placebo‐controlled, single‐dose escalation study, ribozyme was administered as a 4‐hour IV infusion of 10 or 30 mg/m2 or as a SC bolus of 20 mg/m2. Peak ribozyme plasma concentrations of 1.5 and 3.8 μg/mL were observed after the 10 and 30 mg/m2 IV infusions, respectively. When normalized to dose, AUC values as well as peak concentrations increased proportionally as the dose was increased from 10 to 30 mg/m2. Peak concentrations of 0.9 μg/mL were observed approximately 3.25 hours after a 20 mg/m2 SC bolus of ribozyme. The dose‐normalized AUCs obtained after SC dosing were compared to the mean dose‐normalized AUC after IV dosing to estimate an absolute SC bioavailability (f) of approximately 69%. An average elimination half‐life of 28 to 40 minutes was observed after IV administration, which increased to 209 minutes after SC administration. Only 4 of 12 reported adverse events were possibly related to administration of ribozyme (headache and somnolence). Thus, ribozyme administration was well tolerated after a single 4‐hour IV infusion of up to 30 mg/m2 or a single SC bolus of 20 mg/m2.