Pharmacokinetics and tolerability of an antiangiogenic ribozyme (ANGIOZYME(TM)) in healthy volunteers

The pharmacokinetics and tolerability of a chemically stabilized synthetic ribozyme (ANGIOZYME(TM)) targeting the Flt-1 VEGF receptor mRNA were evalua ted 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/m(2 ) or as a SC bolus of 20 mg/m(2). Peak ribozyme plasma concentrations of 1. 5 and 3.8 mug/mL were observed after the 10 and 30 mg/m(2) TV infusions, re spectively. when normalized to dose, A UC values as well as peak concentrat ions increased proportionally as the dose was increased from 10 to 30 mg/m( 2). Peak concentrations of 0.9 mug/mL were observed approximately 3.25 hour s after a 20 mg/m(2) SC bolus of ribozyme. The dose-normalized AUGs obtaine d after SC dosing were compared to the mean dose-normalized AUC after IV do sing to estimate an absolute SC bioavailability (f) of approximately 69%. A n average elimination half-life of 28 to 40 minutes was observed after IV a dministration, 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/m(2) or a singl e SC bolus of 20 mg/m(2). (C)2000 the American College of Clinical Pharmaco logy.