PHASE-I SAFETY AND PHARMACOKINETIC PROFILE OF AN INTERCELLULAR-ADHESION MOLECULE-1 ANTISENSE OLIGODEOXYNUCLEOTIDE (ISIS-2302)

Healthy male volunteers received single or multiple intravenous infusi ons of an intercellular adhesion molecule-1 antisense phosphorothioate oligodeoxynucleotide, ISIS 2302, in a rising-dose (0.06-2.00 mg/kg in fused over 2 hr), double-blind, placebo-controlled trial. Brief, dose- related increases in activated partial thromboplastin time were seen a t the time of peak plasma concentration (C-max). Clinically insignific ant increases in C3a were seen after higher, repeated doses, but C5a, blood pressure and pulse were unaffected. No adverse events or other l aboratory abnormalities were related to treatment with the drug. ISIS 2302 C-max was linearly related to dose and occurred at the end of inf usion. Plasma half-life for intact drug (53-54 min) and total oligonuc leotide (67-74 min) were similar at the two doses (0.5 and 2.0 mg/kg) at which extensive pharmacokinetic data were collected. Nonlinear chan ges in area under the plasma concentration/time curve and steady-state volume of distribution with increasing dose suggested a saturable com ponent to disposition. Metabolites co-migrating with n-1, n-2 and n-3 chain-shortened versions of ISIS 2302 appeared very rapidly in plasma, and disposition and metabolism appeared unaltered by repeated dosing. ISIS 2302 was well tolerated and behaved reproducibly with respect to plasma pharmacokinetics and expected side effects.