Pharmacokinetics and tolerability of intravenous Trecovirsen (GEM (R) 91),an antisense phosphorothioate oligonucleotide, in HIV-positive subjects

Trecovirsen, a 25-mer antisense phosphorothioate oligonucleotide targeted a t the gag site of the HIV gene, was administered to HN-positive volunteers as an IV infusion. Single doses ranged from 0.1 to 2.5 mg/kg in an ascendin g escalation in cohorts of 6 to 22 subjects. Plasma trecovirsen concentrati ons and pharmacokinetic parameters could be assessed at doses greater than or equal to 0.3 mg/kg. Peak plasma concentrations and AUC values increased disproportionately with increasing dose while elimination half-life increas ed and plasma clearance decreased, indicating a saturable process over this dose range. The only significant adverse event observed was an isolated, t ransitory increase in activated partial thromboplastin time at doses greate r than or equal to 2.0 mg/kg that was related to plasma trecovirsen concent rations and is attributed to the polyanionic character of the molecule. Thu s, trecovirsen administration was well tolerated in single IV doses up to 2 .5 mg/kg Journal of Clinical Pharmacology, 1999;39:47-54 (C) 1999 the Ameri can College of Clinical Pharmacology.