REPEAT-DOSE TOXICITY AND PHARMACOKINETICS OF A PARTIAL PHOSPHOROTHIOATE ANTI-HIV OLIGONUCLEOTIDE (AR177) AFTER BOLUS INTRAVENOUS ADMINISTRATION TO CYNOMOLGUS MONKEYS .2.

5'GTGGTGGGTGGGTGGGT-3' (AR177) is a partial phosphorothioate, 17-mer o ligonucleotide that has been shown to have anti-human immunodeficiency virus (HIV) activity in vitro and to be a potent inhibitor of HIV-1 i ntegrase. A repeat-dose toxicity and pharmacokinetic study was conduct ed in which cynomolgus monkeys were given bolus i.v. injections of 2.5 , 10 or 40 mg AR177/kg/day every other day for a total of 12 doses. Co ntrol monkeys received saline. ECG, clinical chemistry, hematology, co agulation parameters, histopathology and the AR177 plasma concentratio n were evaluated. AR177 did not cause any mortality in this study, nor did it cause changes in ECG, clinical chemistry, hematology values or histology. However, there was a dose-dependent inhibition of coagulat ion measured by a prolongation of activated partial thromboplastin tim e; this inhibition was reversible with drug washout. Analysis of plasm a samples by HPLC demonstrated that there was no difference between th e AR177 plasma concentrations that were achieved after the 1st and 12t h (last) doses of 2.5, 10 or 40 mg/kg. There was a direct relationship between the AR177 plasma concentration and activated partial thrombop lastin time. These results indicate that repeated bolus i.v. administr ation of AR177 to cynomolgus monkeys at doses as high as 40 mg/kg was well tolerated and was not associated with the serious cardiovascular responses previously observed with other oligonucleotides administered i.v.