A NOVEL OLIGODEOXYNUCLEOTIDE INHIBITOR OF THROMBIN .2. PHARMACOKINETICS IN THE CYNOMOLGUS MONKEY

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.