Abstract
Tedizolid (TZD) is a novel oxazolidinone antibiotic. Although TZD efficacy correlates with area under the concentration-time curve/minimum inhibitory concentration, there is no report of pharmacokinetic/pharmacodynamic analysis using plasma free TZD concentrations. Several methods have been developed for measuring total TZD concentration, but not for free TZD concentration. We aimed to develop a high-throughput simultaneous quantification method for total and free TZD concentrations using ultra-high-performance liquid chromatography coupled with tandem mass spectrometry (UHPLC-MS/MS). The equilibrium dialysis method was used for separation of the free fraction. Pretreatment was conducted by solid-phase extraction using 96-well HLB µElution plate. Chromatographic separation of the analytes was conducted using a C18 column. MS/MS transitions were monitored in the positive ion mode. Full validation was performed in accordance with the bioanalytical method validation guidance prepared by the US Food and Drug Administration (FDA). The assay showed good linearity over wide ranges of 5–5000 (r2 = 0.9964) and 1.5–1500 (r2 = 0.9990) ng/mL for total and free TZD concentrations, respectively. Within-batch accuracy and precision as well as batch-to-batch accuracy and precision for total and free concentrations fulfilled the criteria of the FDA guidance. The recovery rates were higher than 92.3% and higher than 85.3% for total and free concentrations. Matrix effect showed no remarkable differences among three quality control levels for total and free concentrations. In vitro protein binding rates of TZD ranged from 71.6% to 76.9%, indicating no concentration-dependent difference within the calibration ranges. The total and free concentrations in five patients who received TZD were within the ranges of the calibration curves, demonstrating the feasibility of clinical application of the novel method. In conclusion, we have succeeded to develop for the first time a method for simultaneous quantification of total and free TZD concentrations.
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