Population Pharmacokinetics of Bedaquiline and Metabolite M2 in Patients With Drug-Resistant Tuberculosis: The Effect of Time-Varying Weight and Albumin

E M Svensson, A-G Dosne, M O Karlsson, E M Svensson, A-G Dosne, M O Karlsson

Abstract

Albumin concentration and body weight are altered in patients with multidrug-resistant tuberculosis (MDR-TB) and change during the long treatment period, potentially affecting drug disposition. We here describe the pharmacokinetics (PKs) of the novel anti-TB drug bedaquiline and its metabolite M2 in 335 patients with MDR-TB receiving 24 weeks of bedaquiline on top of a longer individualized background regimen. Semiphysiological models were developed to characterize the changes in weight and albumin over time. Bedaquiline and M2 disposition were well described by three and one-compartment models, respectively. Weight and albumin were correlated, typically increasing after the start of treatment, and significantly affected bedaquiline and M2 plasma disposition. Additionally, age and race were significant covariates, whereas concomitant human immunodeficiency virus (HIV) infection, sex, or having extensively drug-resistant TB was not. This is the first population model simultaneously characterizing bedaquiline and M2 PKs in its intended use population. The developed model will be used for efficacy and safety exposure-response analyses.

© 2016 The Authors CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.

Figures

Figure 1
Figure 1
Visual predictive check showing the 2.5th, 50th, and 97.5th percentiles (lines) of observed albumin concentration and body weights (dots) and the 95% confidence intervals (shaded areas) of the same percentiles from model‐simulated data.
Figure 2
Figure 2
Examples of individual fits from three patients with distinctly different profiles: typical increase (ID1), less common decrease (ID2), or relatively constant (ID3) albumin concentrations.
Figure 3
Figure 3
Prediction and variability corrected visual predictive checks showing the 2.5th, 50th, and 97.5th percentiles (lines) for observed bedaquiline (BDQ) and M2 concentrations and the 95% confidence intervals (shaded areas) of the same percentiles from model‐simulated data over time after the start of treatment (upper panel 0–24 weeks and middle panel 24–96 weeks) and over time after dose (lower panel).
Figure 4
Figure 4
Illustration of covariate relationships included on bedaquiline (BDQ) clearance (CL) and central volume of distribution (V) in the final model. For CL the solid and dotted lines represent the typical values for non‐black and black patients, respectively. For V, the solid line is the typical value. The shaded areas are the 95% confidence interval of the interindividual variability. The lines at the bottom of the graphs represent observed covariate values at the start of treatment.

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