Category: Fellows Posters
Linezolid (LZD) is a widely used antimicrobial that is active against a broad range of disease-causing bacteria. The risk of myelosuppression with LZD is dose- and duration-limiting and occurs more frequently in patients with renal impairment. Accumulation of LZD and its primary metabolites (PNU-142300 and PNU-142586) in patients with renal impairment may contribute to this risk but have not been evaluated as analytical standards of these metabolites are not available. The purpose of this study was to develop an assay and measure serum concentrations of LZD, PNU-142300, and PNU-142586 in patients with renal impairment compared to those without renal impairment.
Chromatographic separation of analytes was accomplished with Waters X-bridge column (C18, 150 x 4.6 mm, 3.5 µm) at 25˚C and subjected to mass analysis using positive electro-spray ionization. The mobile phase A was water with 0.1% formic acid, and mobile phase B was acetonitrile with 0.1% formic acid at a flow rate of 0.6 mL/min, within a 15 min run. Standard curves were linear and correlation coefficients (r2) were ≥0.99 over the concentration ranges. Samples from 10 patients (5 with renal impairment) were assayed. Mean (SD) LZD, PNU-142300 and PNU-142586 trough concentrations were 19.4(6.8), 11.6(6.8), 25.7(16.4) mg/L, respectively, in patients with renal impairment. These values were 2.5-, 5.8-, and 6.8-fold higher for LZD, PNU-142300 and PNU-142586, respectively compared to patients without renal impairment. Peak concentrations showed similar trends for PNU-142300 and PNU-142586 but not LZD, which was similar between groups.
A sensitive LC-MS/MS method to measure LZD and its two primary metabolites was developed and effectively applied to measure these analytes in serum. Patients with renal impairment have substantially higher concentrations of LZD metabolites in human serum compared to patients without renal impairment. Future studies should evaluate the potential combinatorial risk of LZD and its metabolites on myelosuppression in order to mitigate this risk in patients with renal impairment.