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 i.v. infusion of 10 or 30 mg/m2 or as a s.c. bolus of 20 mg/m2. Peak ribozyme plasma concentrations of 1.5 and 3.8 micrograms/mL were observed after the 10 and 30 mg/m2 i.v. 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 microgram/mL were observed approximately 3.25 hours after a 20 mg/m2 s.c. bolus of ribozyme. The dose-normalized AUCs obtained after s.c. dosing were compared to the mean dose-normalized AUC after i.v. dosing to estimate an absolute s.c. bioavailability (f) of approximately 69%. An average elimination half-life of 28 to 40 minutes was observed after i.v. administration, which increased to 209 minutes after s.c. 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 i.v. infusion of up to 30 mg/m2 or a single s.c. bolus of 20 mg/m2.