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Linezolid pharmacokinetics in MDR-TB: a systematic review, meta-analysis and Monte Carlo simulation

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Millard, James, Pertinez, Henry, Bonnett, Laura, Hodel, EvaMaria ORCID: https://orcid.org/0000-0001-5821-1685, Dartois, Véronique, Johnson, John L, Caws, Maxine ORCID: https://orcid.org/0000-0002-9109-350X, Tiberi, Simon, Bolhuis, Mathieu, Alffenaar, Jan-Willem C, Davies, Geraint and Sloan, Derek (2018) 'Linezolid pharmacokinetics in MDR-TB: a systematic review, meta-analysis and Monte Carlo simulation'. The Journal of Antimicrobial Chemotherapy, Vol 73, Issue 1, pp. 1755-1762.

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Abstract

Objectives

The oxazolidinone linezolid is an effective component of drug-resistant TB treatment, but its use is limited by toxicity and the optimum dose is uncertain. Current strategies are not informed by clinical pharmacokinetic (PK)/pharmacodynamic (PD) data; we aimed to address this gap.

Methods

We defined linezolid PK/PD targets for efficacy (fAUC0–24:MIC >119 mg/L/h) and safety (fCmin <1.38 mg/L). We extracted individual-level linezolid PK data from existing studies on TB patients and performed meta-analysis, producing summary estimates of fAUC0–24 and fCmin for published doses. Combining these with a published MIC distribution, we performed Monte Carlo simulations of target attainment.

Results

The efficacy target was attained in all simulated individuals at 300 mg q12h and 600 mg q12h, but only 20.7% missed the safety target at 300 mg q12h versus 98.5% at 600 mg q12h. Although suggesting 300 mg q12h should be used preferentially, these data were reliant on a single centre. Efficacy and safety targets were missed by 41.0% and 24.2%, respectively, at 300 mg q24h and by 44.6% and 27.5%, respectively, at 600 mg q24h. However, the confounding effect of between-study heterogeneity on target attainment for q24h regimens was considerable.

Conclusions

Linezolid dosing at 300 mg q12h may retain the efficacy of the 600 mg q12h licensed dosing with improved safety. Data to evaluate commonly used 300 mg q24h and 600 mg q24h doses are limited. Comprehensive, prospectively obtained PK/PD data for linezolid doses in drug-resistant TB treatment are required.

Item Type: Article
Subjects: QV Pharmacology > Anti-Inflammatory Agents. Anti-Infective Agents. Antineoplastic Agents > QV 268 Antitubercular agents. Antitubercular antibiotics
QV Pharmacology > QV 38 Drug action.
WF Respiratory System > Tuberculosis > WF 205 Epidemiology
WF Respiratory System > Tuberculosis > WF 360 Drug therapy
Faculty: Department: Clinical Sciences & International Health > Clinical Sciences Department
Digital Object Identifer (DOI): https://doi.org/10.1093/jac/dky096
SWORD Depositor: JISC Pubrouter
Depositing User: JISC Pubrouter
Date Deposited: 29 Mar 2018 14:42
Last Modified: 20 Jul 2018 10:56
URI: http://archive.lstmed.ac.uk/id/eprint/8422

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