Dried Blood Spot Analysis for Therapeutic Drug Monitoring of Linezolid in Patients with Multidrug-Resistant Tuberculosis

Abstract

dLinezolid 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.

Clarithromycin increases linezolid exposure in multidrug-resistant tuberculosis patients

“…Therapeutic drug monitoring could help in assessing the linezolid dose after dose reduction [12], especially since the observed drug-drug interaction shows a large interpatient variability. In limited-resource settings, dried blood spot sampling could resolve logistical problems encountered with conventional therapeutic drug monitoring [31].…”

Linezolid tolerability in multidrug-resistant tuberculosis: a retrospective study

“…International collaboration in MDR/XDR-TB research will probably become critically important to facilitate the merging of data to provide large cohort sizes that can be used to explore important clinical questions, such as: what is the role of linezolid drug exposure in the treatment of MDR-TB? Perhaps linezolid dried blood spot [14] or a limited sampling strategy [15] could facilitate TDM in such studies to assess linezolid drug exposure.…”

Role of Therapeutic Drug Monitoring in Pulmonary Infections: Use and Potential for Expanded Use of Dried Blood Spot Samples

“…423 TDM of amphotericin B is not recommended, this drug is not suspected for drug interactions, nor 424 are dose adjustments required in patients with renal impairment [76]. Caspofungin is a poor 425 substrate for CYP450 and therefore only strong inhibitors or inducers will influence the plasma 426 concentration of caspofungin [77]. TDM is only recommended in individual cases when there are 427 pharmacokinetic changes or drug-interactions [78].…”