Limited sampling strategies for therapeutic drug monitoring of linezolid in patients with multidrug-resistant tuberculosis.

Abstract

INTRODUCTION:

Linezolid is a potential drug for the treatment of multidrug-resistant tuberculosis but its use is limited because of severe adverse effects such as anemia, thrombocytopenia, and peripheral neuropathy. This study aimed to develop a model for the prediction of linezolid area under the plasma concentration-time curve from 0 to 12 hours (AUC0-12h) by limited sampling strategy to enable individualized dosing.

PATIENTS AND METHODS:

Fourteen patients with multidrug-resistant tuberculosis received linezolid twice daily as part of their antituberculosis treatment. Linezolid concentrations were determined at steady state by high-performance liquid chromatography tandem mass spectrometry before and at 1, 2, 4, 8, and 12 hours after dosing. Linezolid AUC0-12h population model and limited sampling models were calculated with MWPharm software. The correlation between predicted linezolid AUC0-12h and observed linezolid AUC0-12h was investigated by Bland-Altman analysis.

RESULTS:

A total of 26 pharmacokinetic profiles were obtained. The median AUC0-12h was 51.8 (interquartile range, 41.8-65.9) mg*h/L at 300 mg and 123.8 (interquartile range, 100.9-152.5) mg*h/L at 600 mg, both twice daily. The most relevant model clinically for prediction of linezolid AUC0-12h used a linezolid trough concentration (r = 0.91, prediction bias = -2.9% and root mean square error = 15%).

DISCUSSION:

The difference between choosing a trough concentration and two to three samples increased the correlation from 0.90 to 0.95 but appeared not clinically relevant because it did not result in different dosing advice.

CONCLUSION:

This study showed that linezolid AUC0-12h in patients with multidrug-resistant tuberculosis could be predicted accurately by a minimal sampling strategy and could be used to individualize the dose.

• Authors: Jan-Willem C Alffenaar, Jos G W Kosterink, Richard van Altena, Tjip S van der Werf, Donald R A Uges, Johannes H Proost
• Journal: Therapeutic drug monitoring (Ther Drug Monit) Vol. 32 Issue 1 Pg. 97-101 (Feb 2010) ISSN: 1536-3694 [Electronic] United States
• PMID: 20042919 (Publication Type: Clinical Trial, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Acetamides
• Anti-Infective Agents
• Oxazolidinones
• Linezolid

Topics

• Acetamides (pharmacokinetics, therapeutic use)
• Adult
• Anti-Infective Agents (pharmacokinetics, therapeutic use)
• Area Under Curve
• Chromatography, High Pressure Liquid (methods)
• Drug Monitoring (methods)
• Humans
• Linezolid
• Oxazolidinones (pharmacokinetics, therapeutic use)
• Prospective Studies
• Tandem Mass Spectrometry (methods)
• Tuberculosis, Multidrug-Resistant (drug therapy)
• Young Adult