Population pharmacokinetics and target attainment analysis of linezolid in multidrug-resistant tuberculosis patients.

Abstract

AIM:

This study investigates the pharmacokinetic/pharmacodynamic (PK/PD) target attainment of linezolid in patients infected with multidrug-resistant (MDR) tuberculosis (TB).

METHODS:

A pharmacometric model was developed including 244 timed linezolid concentration samples from 39 patients employing NONMEM 7.4. The probability of target attainment (PTA, PK/PD target: unbound (f) area-under-the-concentration-time-curve (AUC)/minimal inhibitory concentration (MIC) of 119) as well as a region-specific cumulative fraction of response (CFR) were estimated for different dosing regimens.

RESULTS:

A one-compartment model with linear elimination with a clearance (CL) of 7.69 L/h (interindividual variability 34.1%), a volume of distribution (Vd) of 45.2 L and an absorption constant (KA) of 0.679 h-1 (interoccasion variability 143.7%) allometric scaled by weight best described the PK of linezolid. The PTA at an MIC of 0.5 mg/L was 55% or 97% if patients receiving 300 or 600 mg twice daily, respectively. CFRs varied greatly among populations and geographic regions. A desirable global CFR of ≥90% was achieved if linezolid was administered at a dose of 600 mg twice daily but not at a dose of 300 mg twice daily.

CONCLUSION:

This study showed that a dose of 300 mg twice daily of linezolid might not be sufficient to treat MDR-TB patients from a PK/PD perspective. Thus, it might be recommendable to start with a higher dose of 600 mg twice daily to ensure PK/PD target attainment. Hereby, therapeutic drug monitoring and MIC determination should be performed to control PK/PD target attainment as linezolid shows high variability in its PK in the TB population.

• Authors: Anna K Tietjen, Niklas Kroemer, Dario Cattaneo, Sara Baldelli, Sebastian G Wicha
• Journal: British journal of clinical pharmacology (Br J Clin Pharmacol) Vol. 88 Issue 4 Pg. 1835-1844 (02 2022) ISSN: 1365-2125 [Electronic] England
• PMID: 34622478 (Publication Type: Journal Article)
• Copyright: © 2021 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.

Chemical References

• Anti-Bacterial Agents
• Linezolid

Topics

• Anti-Bacterial Agents (pharmacokinetics)
• Drug Monitoring
• Humans
• Linezolid (therapeutic use)
• Microbial Sensitivity Tests
• Probability
• Tuberculosis, Multidrug-Resistant (drug therapy)