Acute toxicology and pharmacokinetic assessment of a ribozyme (ANGIOZYME) targeting vascular endothelial growth factor receptor mRNA in the cynomolgus monkey.
The potential acute toxicity of a ribozyme (ANGIOZYME) targeting the flt-1 vascular endothelial growth factor (VEGF) receptor mRNA was evaluated in cynomolgus monkeys following i.v. infusion or s.c. injection. ANGIOZYME was 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, electrocardiogram (ECG), clinical chemistry, hematology, complement factors, coagulation parameters, and ribozyme plasma concentrations. ANGIOZYME was well tolerated, with no drug-associated morbidity or mortality. There was no clear evidence of ANGIOZYME-related adverse effects in this study. Slight increases in spleen weight and lymphoid hyperplasia were observed in several animals. However, these changes were not dose dependent. Steady-state concentrations of ANGIOZYME were achieved during the 4-hour infusion of 10, 30, or 100 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 sampling period. Monkeys in this toxicology study received significant plasma ANGIOZYME exposure by both the s.c. and i.v. routes.
Sandberg
J A
JA
Ribozyme Pharmaceuticals, Inc., Boulder, CO 80301, USA.
Sproul
C D
CD
Blanchard
K S
KS
Bellon
L
L
Sweedler
D
D
Powell
J A
JA
Caputo
F A
FA
Kornbrust
D J
DJ
Parker
V P
VP
Parry
T J
TJ
Blatt
L M
LM
D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000633:toxicity; D000818:Animals; D001774:Blood Chemical Analysis; D001779:Blood Coagulation Factors / Q000032:analysis; D002851:Chromatography, High Pressure Liquid; D003165:Complement System Proteins / Q000032:analysis; D004334:Drug Administration Schedule; D005260:Female; D018390:Gene Targeting; D007262:Infusions, Intravenous; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D008252:Macaca fascicularis; D008297:Male; D016337:RNA, Catalytic / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity*; D012333:RNA, Messenger / Q000235:genetics*; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism*; D017978:Receptors, Growth Factor / Q000235:genetics* / Q000378:metabolism*; D040262:Receptors, Vascular Endothelial Growth Factor
D020533:Angiogenesis Inhibitors; C121301:Angiozyme; D001779:Blood Coagulation Factors; D016337:RNA, Catalytic; D012333:RNA, Messenger; D017978:Receptors, Growth Factor; D003165:Complement System Proteins; D020794:Receptor Protein-Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor