Repeat-dose toxicity and pharmacokinetics of a partial phosphorothioate anti-HIV oligonucleotide (AR177) after bolus intravenous administration to cynomolgus monkeys.

5'GTGGTGGGTGGGTGGGT-3' (AR177) is a partial phosphorothioate, 17-mer oligonucleotide that has been shown to have anti-human immunodeficiency virus (HIV) activity in vitro and to be a potent inhibitor of HIV-1 integrase. A repeat-dose toxicity and pharmacokinetic study was conducted 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. Control monkeys received saline. ECG, clinical chemistry, hematology, coagulation parameters, histopathology and the AR177 plasma concentration 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 coagulation measured by a prolongation of activated partial thromboplastin time; this inhibition was reversible with drug washout. Analysis of plasma samples by HPLC demonstrated that there was no difference between the AR177 plasma concentrations that were achieved after the 1st and 12th (last) doses of 2.5, 10 or 40 mg/kg. There was a direct relationship between the AR177 plasma concentration and activated partial thromboplastin time. These results indicate that repeated bolus i.v. administration 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.