title: Pharmacokinetics and tolerability of an antiangiogenic ribozyme (ANGIOZYME) in healthy volunteers.
abstract: 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.
authors.affiliation: Ribozyme Pharmaceuticals, Inc., 2950 Wilderness Place, Boulder, Colorado 80301, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Sandberg
authors.forename: V P
authors.initials: VP
authors.lastname: Parker
authors.forename: K S
authors.initials: KS
authors.lastname: Blanchard
authors.forename: D
authors.initials: D
authors.lastname: Sweedler
authors.forename: J A
authors.initials: JA
authors.lastname: Powell
authors.forename: A
authors.initials: A
authors.lastname: Kachensky
authors.forename: L
authors.initials: L
authors.lastname: Bellon
authors.forename: N
authors.initials: N
authors.lastname: Usman
authors.forename: T
authors.initials: T
authors.lastname: Rossing
authors.forename: E
authors.initials: E
authors.lastname: Borden
authors.forename: L M
authors.initials: LM
authors.lastname: Blatt
mesh_terms: D000328:Adult; D020533:Angiogenesis Inhibitors / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D016337:RNA, Catalytic / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*
chemical_list: D020533:Angiogenesis Inhibitors; C121301:Angiozyme; D016337:RNA, Catalytic