Comparison of the pharmacokinetics of subcutaneous and intravenous administration of a phosphorothioate oligodeoxynucleotide in cynomolgus monkeys

The pharmacokinetics of subcutaneous (s.c,) administration of a phosphoroth ioate oligodeoxynucleotide (PS-ODN) was evaluated in cynomolgus monkeys. In a single dose study, monkeys were injected s.c. or intravenously (i.v.) wi th doses of either 1 or 5 mg/kg ISIS 2302, The bioavailability of s.c. inje ction ranged from 26% to 55% and appeared to be dependent on the concentrat ion of the dosing solution rather than the dose, The bioavailability of a s ubcutaneously administered 5 mg/kg dose of ISIS 2302 was 55% using a 50 mg/ ml dosing solution and only 26% using a 10 mg/ml dosing solution. Slow abso rption from the s.c, injection site significantly blunted the maximal conce ntration (C-max) compared with i.v. administration. The time to peak plasma concentration (T-max) increased slightly with increasing dose, from 0.5 to 1 hour for the 1 mg/kg dose to 1 to 2.5 hours for the 5 mg/kg dose. Plasma half-lives were prolonged after s.c. administration, indicating more depen dence on absorption than elimination. The half-lives after s.c. administrat ion averaged 3 hours, whereas after i.v. administration, the half-lives wer e <1 hour. Metabolism of the ISIS 2302 after s.c. injection was consistent with exonucleolytic cleavage, as previously observed after i.v. administrat ion. In summary, s.c. administration of PS-ODN resulted in prolonged and ex tensive absorption of the ODN.