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

Abstract

Oritavancin is a novel glycopeptide antimicrobial agent with potent in vitro activity against a wide variety of gram-positive bacteria, including multidrug-resistant strains of staphylococci and enterococci. A population pharmacokinetic model was developed to describe the disposition of oritavancin with data from a pooled population of phase 1 healthy subjects and phase 2 and 3 patients with complicated skin and skin structure infections or Staphylococcus aureus bacteremia. In addition, the potential influence of factors such as the subject's age, gender, and clinical laboratory measures on oritavancin disposition was evaluated. Oritavancin was administered as both single-and multiple-dose intravenous (i.v.) infusions in fixed doses ranging from 100 to 800 mg or weight-based doses ranging from 0.02 to 10 mg/kg of body weight, with infusion durations ranging from 0.13 to 6.5 h across all studies. The most robust fit to the data (n ‫؍‬ 6,290 oritavancin plasma concentrations from 560 subjects) was obtained using a three-compartment model with zero-order i.v. infusion and first-order elimination. The model was parameterized using total clearance (CL), volume of central compartment (Vc), distributional clearances from the central to both the first and second peripheral compartments, and volumes of distribution for both the first and second peripheral compartments. Weight and study phase (phase 1 versus phase 2/3) were identified as significant predictors of the interindividual variability in CL, while body surface area and age were significant for Vc. These results suggest that dose modification may be warranted in patients weighing >110 kg. However, the mild nature of the observed relationships for Vc suggest that dosing adjustments are not necessary for elderly patients.

Comparison of the Efficacy and Safety of Oritavancin Front-Loaded Dosing Regimens to Daily Dosing: an Analysis of the SIMPLIFI Trial

“…The range of efficacy in the microbiological subgroups is consistent with that reported in other studies of cSSSI (2,23,44,47). Oritavancin pharmacokinetics are well described by a threecompartment model (42). Mean population-predicted pharmacokinetic parameter estimates for patients from the phase 2 and 3 studies of oritavancin yield ␣, ␤, and ␥ half-lives of 2.0, 31.2, and 393 h, respectively (42).…”

“…Oritavancin pharmacokinetics are well described by a threecompartment model (42). Mean population-predicted pharmacokinetic parameter estimates for patients from the phase 2 and 3 studies of oritavancin yield ␣, ␤, and ␥ half-lives of 2.0, 31.2, and 393 h, respectively (42). Theoretically, oritavancin's pharmacokinetics and pharmacodynamics, combined with its concentration-dependent activity, substantial accumulation, and optimized activity from dose pooling rather than dose fractionation, should enable shorter courses of treatment, with preserved efficacy, than for other anti-MRSA agents that have lower plasma exposure values or shorter half-lives in the central compartment.…”

“…Oritavancin's maximum plasma concentration (C max ) and area under the plasma concentration-time curve (AUC) are linear and dose proportional across administered doses (1 to 1,200 mg) (42). In humans, the mean Ϯ standard deviation (SD) plasma and blister fluid exposure values for oritavancin, measured as AUC 0-24 h , resulting from a single dose of 800 mg were 1,111 Ϯ 316 and 208 Ϯ 76.7 g ⅐ h/ml, respectively (24).…”

“…dosing. Instead, it is slowly excreted, unchanged, in both the urine and the feces (terminal half-life ϭ 393 Ϯ 73.5 h), which means that no dosage adjustment is required for age, or for renal or mild to moderate hepatic dysfunction (42).…”

New Gram-Positive Agents: the Next Generation of Oxazolidinones and Lipoglycopeptides

“…Oritavancin is slowly excreted unchanged in feces and urine, with Ͻ1% and 5% eliminated, respectively, after 2 weeks of collection. The terminal half-life of oritavancin is more than 10 days, allowing for use of a single dose in treating ABSSSIs (27,32). Oritavancin displays concentration-dependent bactericidal activity, with the AUC/ MIC ratio correlating best with activity in animal models of infection (27).…”