A novel oligodeoxynucleotide inhibitor of thrombin. II. Pharmacokinetics in the cynomolgus monkey.
OBJECTIVE
To determine the pharmacokinetics of GS-522, an oligodeoxynucleotide (GGTTGGTGTGGTTGG) inhibitor of thrombin, after constant infusion and bolus administration in the cynomolgus monkey.


METHODS
Using a stability indicating HPLC method, the GS-522 plasma concentration versus time data were obtained after constant infusion (0.1, 0.3, 0.5 mg/kg/min) and bolus administration (11.25 and 22.5 mg/kg). Plasma data after bolus administration was fit to a three-compartment model.


RESULTS
The half-lives for the alpha and beta phases were 1.4 and 5.4 min, respectively. Steady state GS-522 concentrations were reached within 10 minutes after initiation of constant infusions. Termination of infusions resulted in a rapid elimination of GS-522 with an average elimination half-life equal to 1.5 min. The Vss calculated from both the constant infusion and bolus data approximated the blood volume of the monkey. Substitution of the phosphodiester backbone at the 3' end of GS-522 with two phosphorothioate linkages did not substantially effect the elimination half-life upon termination of infusion.


CONCLUSIONS
These data in conjunction with published biodistribution data suggest that oligodeoxynucleotides are rapidly cleared from plasma by tissue uptake and that little efflux back into blood takes place. Additionally, strategies designed to increase oligodeoxynucleotide resistance to exonucleases will not dramatically increase plasma half-lives.
Lee
W A
WA
Gilead Sciences, Inc., Foster City, California 94404, USA.
Fishback
J A
JA
Shaw
J P
JP
Bock
L C
LC
Griffin
L C
LC
Cundy
K C
KC
D000818:Animals; D001483:Base Sequence; D008252:Macaca fascicularis; D008969:Molecular Sequence Data; D009841:Oligonucleotides / Q000378:metabolism*; D013917:Thrombin / Q000378:metabolism*; D013997:Time Factors
D009841:Oligonucleotides; D013917:Thrombin