Ultra-performance liquid chromatography-tandem mass spectrometric method for quantitation of the recently Food and Drug Administration approved combination of vaborbactam and meropenem in human plasma

Abstract

A parenteral medical combination containing vaborbactam and meropenem is used mainly to treat complicated urinary tract infections. A novel ultra-performance liquid chromatography tandem mass spectrometric method was developed for the sensitive determination of both compounds in human plasma. Sample preparation was performed by precipitation technique. The chromatographic separation was accomplished using the Acquity C18-BEH column, 0.01 M ammonium formate: acetonitrile (47 : 53, v/v) as a mobile phase with a flow rate of 0.2 ml min −1 . Analytes were monitored by applying multiple reaction monitoring. The bioanalytical validation criteria were conducted following the Food and Drug Administration recommendations. The method was linear within range 0.5 to 50 µg ml −1 , for both drugs. The intra-day and inter-day precision, as coefficient variation (% CV) and the accuracy, as % bias did not exceed 15% for both drugs. The percentage recovery of targeted analytes was not less than 77%, calculated at three quality control levels. The proposed method showed a suitable lower level of quantification value of 0.50 µg ml −1 for both analytes, which is far lower than the expected C max , which permits the use of this method for pharmacokinetic studies. The proposed method proved to be useful for the evaluation of this combination in both human plasma and pharmaceutical formulation.

Fast and Sensitive Method for Simultaneous Quantification of Meropenem and Vaborbactam in Human Plasma Microsamples by Liquid Chromatography–Tandem Mass Spectrometry for Therapeutic Drug Monitoring

“…The method selectivity was very efficient, as witnessed by the fact that no interference due to endogenous compounds and/or co-administered drugs was observed in the chromatograms of 10 pools of plasma samples obtained by mixing blood drawn from hospitalized patients. This finding was consistent with those observed in other studies measuring MRP and VBR concentrations by means of LC-MS/MS methods [ 18 , 19 ], even if the much smaller plasma sample size used by us (3 vs. 100 μL) may suggest a better absolute sensitivity of our method. The compound-specific MRM transitions used in our methods were similar to those implemented in previous studies [ 18 , 19 ], and this granted high selectivity.…”

“…Our method was very sensitive and allowed reliable quantification of concentrations as low as 0.1 mg/L. This level of sensitivity is the highest in the analysis of MRP and VBR among the available LC-MS/MS techniques [ 18 , 19 ], and was granted in plasma microsamples. This is an added value for TDM purposes, as it ensures accurate precision in the measurement of MRV and VBR plasma concentrations.…”

“…Single-charge positive ion mass transitions were selected for optimal sensitivity and specificity by analyzing the MS/MS fragmentation pattern spectra of analytes (data not shown) and by reviewing the literature [ 17 , 18 , 19 ]. Proton ion adducts of MRP and meropenem-d6 (MRP-d6) were detected by means of the following mass transitions: 384.2–141.0 m / z and 390.2–147.1 m / z and daughter ion intensity over retention time were used to generate multiple reaction monitoring (MRM) ion extraction chromatograms.…”

“…Several high-performance liquid chromatography (HPLC) or mass spectrometry (LC-MS/MS) methods have been developed for measuring MRP in biological fluids, either in plasma [ 8 , 9 , 10 , 11 ] or in serum [ 12 , 13 , 14 , 15 ] However, there are only a few available methods for measuring simultaneously MRP and VBR in biological fluids by means of HPLC [ 8 , 16 ] or of LC-MS/MS methods [ 17 , 18 , 19 ], and all of these are based on traditional blood sampling volume, namely 3–5 mL.…”

Preanalytical Stability of Flucloxacillin, Piperacillin, Tazobactam, Meropenem, Cefalexin, Cefazolin, and Ceftazidime in Therapeutic Drug Monitoring: A Structured Review

“…19 At 2708C, meropenem has been reported to be stable up to 13 months with no reports of instability. [9][10][11]14,15,17,18,20,25,27,28,30,[33][34][35]38,40,41,[55][56][57][58][59] Based on these conflicting data, it appears that meropenem can be considered stable for 6 hours at room temperature, 2 days at 2-88C, and 1 week at 2208C.…”