PT  - JOURNAL ARTICLE
AU  - Geary, Richard S.
AU  - Yu, Rosie Z.
AU  - Watanabe, Tanya
AU  - Henry, Scott P.
AU  - Hardee, Greg E.
AU  - Chappell, Alfred
AU  - Matson, John
AU  - Sasmor, Henri
AU  - Cummins, Len
AU  - Levin, Arthur A.
TI  - PHARMACOKINETICS OF A TUMOR NECROSIS FACTOR-α PHOSPHOROTHIOATE 2′-<em>O</em>-(2-METHOXYETHYL) MODIFIED ANTISENSE OLIGONUCLEOTIDE: COMPARISON ACROSS SPECIES
AID  - 10.1124/dmd.31.11.1419
DP  - 2003 Nov 01
TA  - Drug Metabolism and Disposition
PG  - 1419--1428
VI  - 31
IP  - 11
4099  - http://dmd.aspetjournals.org/content/31/11/1419.short
4100  - http://dmd.aspetjournals.org/content/31/11/1419.full
SO  - Drug Metab Dispos2003 Nov 01; 31
AB  - The pharmacokinetics of a 2′-O-(2-methoxyethyl)-ribose modified phosphorothioate oligonucleotide, ISIS 104838 (human tumor necrosis factor-α antisense), have been characterized in mouse, rat, dog, monkey, and human. Plasma pharmacokinetics after i.v. administration exhibited relatively rapid distribution from plasma to tissues with a distribution half-life estimated from approximately 15 to 45 min in all species. Absorption after s.c. injection was high (80-100%), and absorption after intrajejunal administration in proprietary formulations was as high as 10% bioavailability compared with i.v. administration. Urinary excretion of the parent drug was low, with less than 1% of the administered dose excreted in urine after i.v. infusion in monkeys at clinically relevant doses (≤5 mg/kg). ISIS 104838 is highly bound to plasma proteins, likely preventing renal filtration. However, shortened oligonucleotide metabolites of ISIS 104838 lose their affinity to bind plasma proteins. Thus, excretion of radiolabel (mostly as metabolites) in urine (75%) and feces (5-10%) was nearly complete by 90 days. Elimination of ISIS 104838 from tissue was slow (multiple days) for all species, depending on the tissue or organ. The highest concentrations of ISIS 104838 in tissues were seen in kidney, liver, lymph nodes, bone marrow, and spleen. In general, concentrations of ISIS 104838 were higher in monkey tissues than in rodents at body weight-equivalent doses. Plasma pharmacokinetics scale well across species as a function of body weight alone. This favorable pharmacokinetic profile for ISIS 104838 provides guidance for clinical development and appears to support infrequent and convenient dose administration. The American Society for Pharmacology and Experimental Therapeutics