Wa. Lee et al., A NOVEL OLIGODEOXYNUCLEOTIDE INHIBITOR OF THROMBIN .2. PHARMACOKINETICS IN THE CYNOMOLGUS MONKEY, Pharmaceutical research, 12(12), 1995, pp. 1943-1947
Purpose. To determine the pharmacokinetics of GS-522, an oligodeoxynuc
leotide (GGTTGGTGTGGTTGG) inhibitor of thrombin, after constant infusi
on and bolus administration in the cynomolgus. monkey. Methods. Using
a stability indicating HPLC method, the GS-522 plasma concentration ve
rsus 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. Resul
ts. 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 infu
sions resulted in a rapid elimination of GS-522 with an average elimin
ation half-life equal to 1.5 min. The V-ss calculated from both the co
nstant infusion and bolus data approximated the blood Volume of the mo
nkey. Substitution of the phosphodiester backbone at the 3' end of GS-
522 with two phosphorothioate linkages did not substantially effect th
e elimination half-life upon termination of infusion. Conclusions. The
se data in conjunction with published biodistribution data suggest tha
t oligodeoxynucleotides are rapidly cleared from plasma by tissue upta
ke and that little efflux back into blood takes place. Additionally, s
trategies designed to increase oligodeoxynucleotide resistance to exon
ucleases will not dramatically increase plasma half-lives.