LC-MS application for therapeutic drug monitoring in alternative matrices

•Last five years literature about LC–MS has been checked for this review.•Newest technologies and devices have been deeply described and discussed.•The most innovative, convenient or accurate matrices have been depicted in detail. Nowadays the practice of therapeutic drug monitoring, consisting in the measurement of drugs concentrations in biological matrices in order to guide possible posological adjustments, is becoming more and more important for the management and optimization of several treatments, especially when drugs with narrow therapeutic indexes are administered. Although TDM on plasma samples is currently considered the gold standard, this practice shows some limitations: it requires venous blood sampling, centrifugation and, if necessary, shipment with refrigeration; moreover, drug concentrations in plasma or blood do not necessarily reflect the ones in the target tissues or cells. Therefore, in the recent years great attention has been given to alternative matrices for TDM purpose, in order to reduce invasiveness, costs or to obtain better information about drug concentrations at the active sites. This evolution is strongly sustained by the spreading use of liquid chromatography coupled with mass spectrometry (LC–MS) techniques for the analysis of small molecules, which is constantly increasing sensitivity and specificity of TDM assays. In this review, we present and summarize recently published LC–MS applications providing alternatives to plasma testing, in order to avoid blood withdrawal, plasma separation, refrigerated shipment or, if possible, to obtain better information about drug exposure in target cells. By analyzing the last 5 years of literature, reported in PubMed website, LC–MS/MS applications have been reported, with particular focus on the ones with higher probability to enter in the near future in clinical practice. Microsampling strategies and alternative biological matrices, from urine to tissue samples, have been included.