Pharmacokinetics and safety of an anti-vascular endothelial growth factor aptamer (NX1838) following injection into the vitreous humor of rhesus monkeys.
OBJECTIVE
The objective of this study was to determine the pharmacokinetics and safety for NX1838 following injection into the vitreous humor of rhesus monkeys.


METHODS
Plasma and vitreous humor pharmacokinetics were determined following a single bilateral 0.25, 0.50, 1.0, 1.5, or 2.0 mg/eye dose. In addition, the pharmacokinetics and toxicological properties of NX1838 were determined following six biweekly bilateral injections of 0.25 or 0.50 mg/eye or following four biweekly bilateral injections of 0.10 mg per eye followed by two biweekly bilateral injections of 1.0 mg per eye.


RESULTS
Plasma and vitreous humor NX1838 concentrations were linearly related to the dose administered. NX1838 was cleared intact from the vitreous humor into the plasma with a half-life of approximately 94 h, which was in agreement with the plasma terminal half-life. Vascular endothelial growth factor (VEGF)-binding assays demonstrated that the NX1838 remaining in the vitreous humor after 28 days was fully active. No toxicological effects or antibody responses were evident.


CONCLUSIONS
The no observable effect level was greater than six biweekly bilateral 0.50 mg/eye doses or two biweekly bilateral 1.0 mg/eye doses. These pharmacokinetic and safety data support monthly 1 or 2 mg/eye dose regimens in human clinical trials.
Drolet
D W
DW
Gilead Sciences Inc, Boulder, CO 80301, USA. ddrolet@gilead.com
Nelson
J
J
Tucker
C E
CE
Zack
P M
PM
Nixon
K
K
Bolin
R
R
Judkins
M B
MB
Farmer
J A
JA
Wolf
J L
JL
Gill
S C
SC
Bendele
R A
RA
D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D004435:Eating / Q000187:drug effects; D004596:Electroretinography; D016228:Endothelial Growth Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D007267:Injections; D008222:Lymphokines / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008253:Macaca mulatta; D008297:Male; D009841:Oligonucleotides / Q000494:pharmacology*; D009929:Organ Size / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D014822:Vitreous Body / Q000378:metabolism / Q000502:physiology*
D016228:Endothelial Growth Factors; D008222:Lymphokines; D009841:Oligonucleotides; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; C430291:NX1838