Pharmacokinetics of Oritavancin in Plasma and Skin Blister Fluid following Administration of a 200-Milligram Dose for 3 Days or a Single 800-Milligram Dose

Abstract

Oritavancin is a novel glycopeptide currently being developed for the treatment of complicated skin and skin structure infections (cSSSI), including those caused by multidrug resistant gram-positive pathogens. The disposition of oritavancin in skin structures was investigated using a cantharide-induced blister fluid model. Seventeen healthy male subjects received oritavancin, but only 16 subjects were evaluated after one subject discontinued study drug. Each subject (eight per dose group) received 200 mg of oritavancin once a day for 3 days (group A) or 800 mg as one single dose (group B). Group A plasma samples and exudates from blister fluid were collected on days 3, 4, 7, 9, and 12 and on days 3, 4, 7, and 9, respectively. Group B samples and exudates were collected on days 1, 2, 5, 7, and 10 and on days 1, 2, 5, and 7, respectively. Drug concentrations were determined using a liquid chromatography-tandem mass spectrometry assay and, subsequently, pharmacokinetic analysis was performed. Differences between treatment groups in ratios for area under the concentration-time curve for blister fluid and plasma (AUC blister fluid /AUC plasma ratios) were evaluated using a t test ( The antibacterial spectrum of oritavancin includes Staphylococcus aureus, including methicillin-resistant strains; Staphylococcus epidermidis and other coagulase-negative staphylococci, including methicillin-resistant and some teicoplanin-resistant strains; enterococci, including vancomycin-resistant, teicoplanin-resistant (vanA) isolates of Enterococcus faecium and Enterococcus faecalis and the intrinsically vancomycin-resistant species Enterococcus gallinarum and Enterococcus casseliflavus; and streptococci, including Streptococcus pyogenes and Streptococcus pneumoniae, including penicillin-resistant isolates. Rapid bactericidal in vitro activity against most isolates of E. faecalis and E. faecium is a property of oritavancin that distinguishes it from vancomycin, ampicillin, linezolid, and quinupristin-dalfopristin.A phase 1 study in healthy subjects has demonstrated the elimination of oritavancin to be very slow, with approximately 6% of the dose eliminated from the body within a 1-week period after single-dose intravenous infusion (1). The plasma pharmacokinetics (PK) of oritavancin have been evaluated in several single-and multiple-dose clinical pharmacology studies. Across studies, oritavancin displayed linear pharmacokinetics for weight-based doses ranging from 0.02 to 3 mg/kg of body weight and fixed doses from 100 to 600 mg. Based on population pharmacokinetic analyses, oritavancin plasma concentrations display a multiexponential decline and are well described by a three-compartment model with corresponding apparent tissue distribution (␣ and ␤) and plasma terminal (␥) half-lives of 2.4, 18, and 360 h, respectively (J. S. Owen, S. M. Bhavnani, J. Fiedler-Kelly, J. S. Loutit, S. B. Porter, and L. Phillips, Abstr. 44th Intersci. Conf. Antimicrob. Agents Chemother., abstr. A-20, 2004).Oritavancin has been shown to be effective in tw...

Efficacy of Oritavancin in a Murine Model of Bacillus anthracis Spore Inhalation Anthrax

“…dose of oritavancin 24 h before aerosol challenge underscores the extended half-life of this drug (5,15,27,28). Furthermore, this finding suggests that oritavancin may concentrate in those cellular compartments where spores may germinate in the early stages of infection (24,26).…”

“…For comparison, an oritavancin fAUC 0-24 h of 167 g ⅐ h/ml is predicted in human plasma following a single 800-mg i.v. dose (15), with a human serum protein binding value of 85% (5). Thus, total drug exposures that provide maximal or near-maximal single-dose efficacy in the mouse inhalational anthrax model are clinically relevant.…”

Oritavancin Population Pharmacokinetics in Healthy Subjects and Patients with Complicated Skin and Skin Structure Infections or Bacteremia

“…Numerous phase 1, 2, and 3 studies have been conducted evaluating oritavancin in both healthy subjects and infected patients with cSSSI or Staphylococcus aureus bacteremia (3,8,12). It has been administered as either single-or multiple-dose intravenous (i.v.)…”

“…infusions in fixed doses ranging from 100 to 800 mg or as weight-based doses ranging from 0.02 to 10 mg/kg of body weight. Pharmacokinetic (PK) studies have shown that oritavancin displays linear PKs for weightbased or fixed dose ranges (3,8,12). Additionally, oritavancin was shown to be safe and well tolerated, with no clinically relevant changes in renal, hepatic, or hematological indices compared to the individual's baseline.…”

Impact of Human Serum Albumin on Oritavancin In Vitro Activity against Enterococci

“…Oritavancin concentrations (Table 1) were chosen to approximate the closest MIC doubling dilution to the total (protein bound plus unbound) peak (C max ) and total trough levels in plasma following administration of a 200-mg dose (6,7,13).…”