Population Pharmacokinetics of AZD-5847 in Adults with Pulmonary Tuberculosis

Abstract

AZD-5847 is a new oxazolidinone derivative under development for the treatment of tuberculosis (TB). Here we describe the population pharmacokinetics (PK) of AZD-5847 in patients with tuberculosis based on a recently completed phase II study. The study included 60 patients with drug-susceptible TB. Patients were randomized to four dosages (500 mg once daily, 1,200 mg once daily, 500 mg twice daily, and 800 mg twice daily). Patients were intensively sampled on days 1 and 14. AZD-5847 pharmacokinetics were best described with a two-compartment model with lag time (Tlag) for absorption. AZD-5847 bioavailability was nonlinear and plateaued at 800 mg. We performed deterministic simulation to compare the PK/pharmacodynamics (PD) of AZD-5847, linezolid, and sutezolid. AZD-5847 PK/PD in terms of both area under the concentration-time curve for the free, unbound fraction (fAUC)/MIC and time the free concentration was above the MIC (fT>MIC) were less favorable than those for linezolid and sutezolid. This could help explain the poor bactericidal activity of AZD-5847 in the recent phase II study.

Keywords: AZD-5847; pharmacokinetics; tuberculosis.

Copyright © 2017 American Society for Microbiology.

Figures

FIG 1

Population pharmacokinetic model for day 1 only used to predict concentrations on day 14.

FIG 2

Typical pharmacokinetic profile for AZD-5847.

FIG 3

Goodness-of-fit plots for the final population pharmacokinetic model. The graph on the right shows individual predictions of AZD-5847 versus observed concentrations. The graph on the left shows population predictions of vancomycin versus observed concentrations.

FIG 4

Visual predictive check for AZD-5847 concentration versus time based on 1,000 Monte Carlo simulations. The solid green line represents the 10th, 50th, and 90th percentiles of observed data. The shaded regions represent the 90% confidence interval around the 10th, 50th, and 90th percentiles of simulated data. The blue diamonds are observed concentrations.