Pharmacokinetics, safety, and tolerability of ascending single intravenous doses of oritavancin administered to healthy human subjects

Abstract

Oritavancin (LY333328 diphosphate) is a novel glycopeptide antimicrobial agent with potent microbiological activity in vitro against Gram-positive bacteria. A single-dose, open-label, noncontrolled, dose-escalation study in 11 healthy human subjects was carried out to evaluate the safety and pharmacokinetics of oritavancin. One subject at each dose level received a single intravenous dose of 0.02, 0.03, 0.05, 0.08, 0.125, 0.20, and 0.325 mg/kg infused over 1 hour and four subjects each received a single-dose of 0.5 mg/kg. Safety and tolerability were evaluated by monitoring adverse events and laboratory parameters. Oritavancin pharmacokinetics were assessed by blood, urine, and fecal sampling. The plasma concentrations of oritavancin after the end of infusion followed a multiexponential decline over a 2-week period. Median (range) C max for the 0.5 mg/kg dose group was 6.5 (4.7–7.6) μg/mL. In every subject, plasma concentrations declined to ≤10% of the C max within 24 hours. Following a short, constant-rate infusion, the pharmacokinetics of oritavancin were linear across a total dose range from 3.66–44.6 mg. Renal clearance was approximately 0.457 mL/min. The mean (range) plasma terminal half-life of oritavancin was 195.4 (135.8–273.8) hours across all dose levels from 0.05–0.5 mg/kg. Less than 5% and 1% of administered drug were recovered in the urine and feces, respectively, after 7 days. This first time in man evaluation of oritavancin revealed that single doses of oritavancin of up to and including 0.5 mg/kg were safe and well tolerated. Although no clinically relevant changes in renal, hepatic and hematologic indices from baseline were observed, five subjects did manifest asymptomatic and transient elevations of hepatic transaminase concentrations. Because this study was not placebo-controlled and enrolled a small number of subjects, the safety and pharmacokinetic profiles of oritavancin need to be confirmed in additional studies.