Detection and plasma pharmacokinetics of an anti-vascular endothelial growth factor oligonucleotide-aptamer (NX1838) in rhesus monkeys.
Aptamers are oligonucleotide ligands selected, in vitro, to bind a specified target protein. The first aptamer to reach human clinical testing is NX1838, a polyethylene glycol conjugated aptamer that inhibits vascular endothelial growth factor. This paper describes the validation of a high-performance liquid chromatographic anion-exchange method for the determination of NX1838 in plasma. Measurements of intact NX1838 had a coefficient of variation of less than 8% and an accuracy between 107% and 115%. The assay was utilized to determine NX1838 plasma pharmacokinetics in rhesus monkeys following a single 1 mg/kg intravenous or subcutaneous dose. Following intravenous administration, the maximum achieved plasma concentration was 25.5 microg/ml with a terminal half-life of 9.3 h and clearance rate of 6.2 ml/h. After subcutaneous administration, the fraction of the dose absorbed into the plasma compartment was 0.78 with a time to peak concentration (4.9 microg/ml) of 8 to 12 h.
Tucker
C E
CE
NeXstar Pharmaceuticals Inc., Boulder, CO 80301, USA.
Chen
L S
LS
Judkins
M B
MB
Farmer
J A
JA
Gill
S C
SC
Drolet
D W
DW
D000818:Animals; D002851:Chromatography, High Pressure Liquid / Q000379:methods*; D004355:Drug Stability; D016228:Endothelial Growth Factors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D008222:Lymphokines / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008253:Macaca mulatta; D009841:Oligonucleotides / Q000097:blood* / Q000378:metabolism / Q000493:pharmacokinetics; D011786:Quality Control; D015203:Reproducibility of Results; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D008222:Lymphokines; D009841:Oligonucleotides; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors