Population pharmacokinetic analyses for telavancin using data from healthy subjects and patients with infections.

Abstract

Telavancin is an intravenously administered lipoglycopeptide antibiotic active against clinically relevant gram-positive pathogens. In these analyses, a population pharmacokinetic (PK) model was constructed to describe the time course of telavancin in plasma and epithelial lining fluid (ELF) using data from healthy subjects and patients with complicated skin and skin-structure infections, hospital-acquired and ventilator-associated bacterial pneumonia, or uncomplicated bacteremia across Phases 1-4 of clinical development. Data from 1,205 individuals pooled from 21 studies contributed a total of 9,088 telavancin plasma concentrations. The final model for telavancin was a two-compartment model with zero-order intravenous input and linear elimination. Dialysis clearance was included as part of the base structural PK model; the relationship between telavancin clearance and creatinine clearance was included a priori. Body weight, age, and infection type were identified as statistically significant predictors of the interindividual variability (IIV) in total clearance. Body weight, age, and infection type were also identified as statistically significant predictors of IIV for the central and peripheral volumes of distribution. Only body weight was found to be a significant predictor of the IIV in distributional clearance. The model for ELF did not reveal any appreciable biases and determined the average free-drug ELF penetration ratio to be 73.0%. In summary, the population PK model characterized the time course of telavancin in both plasma and ELF robustly, captured the impact of clinically meaningful patient covariate effects, including removal of drug due to hemodialysis, and provided reliable individual post hoc estimates of exposure in subjects enrolled in the clinical studies.