An isotope-dilution LC-MS/MS method for the simultaneous quantification of meropenem and its open-ring metabolite in serum

Background: Therapeutic drug monitoring (TDM) of beta-lactam antibiotics and, among them, especially meropenem gains importance in the field of laboratory medicine. Meropenem is known to be unstable, resulting in a degradation product with an open beta-lactam ring. For a more comprehensive TDM of meropenem, the aim was to develop a LC-MS/MS method for the simultaneous quantification of meropenem and its main degradation product, the open-ring metabolite (ORM). Methods: The method involves a protein precipitation followed by chromatographic separation using a formic acid-ammonium formate methanol gradient on a pentafluorophenyl column. Multiple reaction monitoring in the positive ion mode and stable isotope labeled internal standards were used for quantification. Validation was performed according to the European Medicines Agency guideline. Results: Validation was successful performed within the linear drug concentration range of 1.0-100.0 mg/l for meropenem and 0.62-62.30 mg/l for the ORM. Investigation of selectivity, accuracy and precision showed good results and potential matrix effects were successfully compensated by the internal standards. The suitability of the method was shown by the comparison of 35 anonymized leftover serum samples from intensive care patients with routine analyses. Conclusion: For the first time, we herein describe a liquid chromatography tandem mass spectrometry (LC-MS/MS) method for the simultaneous quantification of meropenem and its ORM in human serum. The ratio of active to inactive compound provides valuable pharmaceutical and pharmacokinetic information, which may contribute to therapeutic efficacy. (C) 2021 Elsevier B.V. All rights reserved.