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.

FIG. 1.

(A) Semilog scatterplot of oritavancin concentrations versus time since start of last infusion, stratified by dose range, following a single dose of oritavancin. (B) Semilog scatterplot of oritavancin concentrations versus time since start of last infusion, stratified by dose range, following multiple doses of oritavancin.

FIG. 2.

(A) Scatterplot of observed versus individual fitted oritavancin concentrations for the final population PK model. (B) Scatterplot of population weighted residuals versus time since the start of the last infusion for the final population PK model. (C) Scatterplot of individual weighted residuals versus individual fitted oritavancin concentrations for the final population PK model, stratified by population. (D) Scatterplot of the population weighted residuals versus dose for the final population PK model.

FIG. 3.

(A) Scatterplot of dose-normalized C_max versus age (line represents a linear regression fit of the data). (B) Boxplots of predicted, steady-state AUC_0-24 values versus weight categories for two different dosing regimens. The left panel presents the predicted AUC_0-24 when subjects are given 200 mg daily, regardless of body weight. The right panel presents predicted AUC_0-24 when subjects are given 200 mg daily when body weight is less than or equal to 110 kg and 300 mg daily when body weight is greater than 110 kg.