title: Dried blood spot analysis for therapeutic drug monitoring of linezolid in patients with multidrug-resistant tuberculosis.
abstract: Linezolid is a promising antimicrobial agent for the treatment of multidrug-resistant tuberculosis (MDR-TB), but its use is limited by toxicity. Therapeutic drug monitoring (TDM) may help to minimize toxicity while adequate drug exposure is maintained. Conventional plasma sampling and monitoring might be hindered in many parts of the world by logistical problems that may be solved by dried blood spot (DBS) sampling. The aim of this study was to develop and validate a novel method for TDM of linezolid in MDR-TB patients using DBS sampling. Plasma, venous DBS, and capillary DBS specimens were obtained simultaneously from eight patients receiving linezolid. A DBS sampling method was developed and clinically validated by comparing DBS with plasma results using Passing-Bablok regression and Bland-Altman analysis. This study showed that DBS analysis was reproducible and robust. Accuracy and between- and within-day precision values from three validations presented as bias and coefficient of variation (CV) were less than 17.2% for the lower limit of quantification and less than 7.8% for other levels. The method showed a high recovery of approximately 95% and a low matrix effect of less than 8.7%. DBS specimens were stable at 37°C for 2 months and at 50°C for 1 week. The ratio of the concentration of linezolid in DBS samples to that in plasma was 1.2 (95% confidence interval [CI], 1.12 to 1.27). Linezolid exposure calculated from concentrations DBS samples and plasma showed good agreement. In conclusion, DBS analysis of linezolid is a promising tool to optimize linezolid treatment in MDR-TB patients. An easy sampling procedure and high sample stability may facilitate TDM, even in underdeveloped countries with limited resources and where conventional plasma sampling is not feasible.
authors.affiliation: University of Groningen, Department of Pharmacotherapy and Pharmaceutical Care, Groningen, The Netherlands.
authors.forename: D H
authors.initials: DH
authors.lastname: Vu
authors.forename: M S
authors.initials: MS
authors.lastname: Bolhuis
authors.forename: R A
authors.initials: RA
authors.lastname: Koster
authors.forename: B
authors.initials: B
authors.lastname: Greijdanus
authors.forename: W C M
authors.initials: WC
authors.lastname: de Lange
authors.forename: R
authors.initials: R
authors.lastname: van Altena
authors.forename: J R B J
authors.initials: JR
authors.lastname: Brouwers
authors.forename: D R A
authors.initials: DR
authors.lastname: Uges
authors.forename: J W C
authors.initials: JW
authors.lastname: Alffenaar
mesh_terms: D000081:Acetamides / Q000097:blood* / Q000493:pharmacokinetics / Q000494:pharmacology; D000328:Adult; D000995:Antitubercular Agents / Q000097:blood* / Q000493:pharmacokinetics / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D059788:Dried Blood Spot Testing; D016903:Drug Monitoring / Q000379:methods*; D005260:Female; D006801:Humans; D000069349:Linezolid; D008297:Male; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000254:growth & development; D023303:Oxazolidinones / Q000097:blood* / Q000493:pharmacokinetics / Q000494:pharmacology; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D053719:Tandem Mass Spectrometry; D018088:Tuberculosis, Multidrug-Resistant / Q000097:blood* / Q000188:drug therapy* / Q000382:microbiology
chemical_list: D000081:Acetamides; D000995:Antitubercular Agents; D023303:Oxazolidinones; D000069349:Linezolid