Quantitation of meropenem in dried blood spots using microfluidic-based volumetric sampling coupled with LC-MS/MS bioanalysis in preterm neonates

Abstract

Meropenem, a carbapenem antibiotic, has been used for empirical and definitive therapy of severe infections for many years. Therapeutic drug monitoring (TDM) plays an indispensable role in the individualization of meropenem particularly in the preterm neonates, a population in which adjusting proper dosages has always been one of the most challenging tasks for their growth changes. In this report, a simple and accurate method for the quantitative analysis of meropenem in dried blood spot (DBS) samples by LC-MS/MS was developed. The traditional DBS drawbacks were conquered in this study by combining microfluidic-based volumetric sampling, shorten drying procedure, and sensitive detection. Moreover, the on-card stability of meropenem was improved obviously. The DBS-based method validation included hematocrit (Hct) effect, selectivity, carry-over, linearity, accuracy, precision, matrix effect, recovery and stability (high temperature and humidity). The calibration linear range of meropenem was 0.3-100 µg/mL. The acceptance criteria of accuracy (relative error < 4.53 %) and precision (coefficient of variation < 8.63 %) were met in all levels of quality control samples. The DBS samples was stable at 40 °C for 12 h, room temperature for 1 day, 4 °C for 7 days, -20 °C for 14 days and -40 °C for 30 days, respectively. A good correlation was observed between DBS concentration and plasma concentration of meropenem. There was 93.4 % of the samples between estimated plasma concentration and plasma concentration within 20 % of the mean of concentration, and no significant Hct effect was observed on the quantification. It has been successfully applied to samples derived from preterm neonates with severe infections. The supported data indicated that the DBS-based method using microfluidic-based volumetric sampling could be an alternative strategy to carry on TDM of meropenem in preterm neonates, with satisfactory performance and logistics advantages.

Keywords: Dried blood spot; LC-MS/MS; Meropenem; Microfluidic-based volumetric sampling; Therapeutic drug monitoring.