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


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%).


CONCLUSIONS
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.


CONCLUSIONS
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.
Alffenaar
Jan-Willem C
JW
Department of Hospital and Clinical Pharmacy, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. j.w.c.alffenaar@apoth.umcg.nl
Kosterink
Jos G W
JG
van Altena
Richard
R
van der Werf
Tjip S
TS
Uges
Donald R A
DR
Proost
Johannes H
JH
D000081:Acetamides / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000328:Adult; D000890:Anti-Infective Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019540:Area Under Curve; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D016903:Drug Monitoring / Q000379:methods; D006801:Humans; D000069349:Linezolid; D023303:Oxazolidinones / Q000493:pharmacokinetics* / Q000627:therapeutic use; D011446:Prospective Studies; D053719:Tandem Mass Spectrometry / Q000379:methods; D018088:Tuberculosis, Multidrug-Resistant / Q000188:drug therapy*; D055815:Young Adult
D000081:Acetamides; D000890:Anti-Infective Agents; D023303:Oxazolidinones; D000069349:Linezolid