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Although a few data sets regarding enalapril, its metabolite enalaprilat and carvedilol in children have been published, pharmacokinetic data on carvedilol metabolites are missing. However, for both drug substances, their active metabolites contribute substantially to drug efficacy. As data can hardly be derived from adults owing to the unknown impacts of enzymatic maturation and ontogeny during childhood, customised assays are important to facilitate paediatric evidence\u2010based pharmacotherapy. Considering ethical paediatric constraints, a low\u2010volume liquid chromatography coupled to mass spectrometry (LC\u2013MS\/MS) assay was developed using whole blood or plasma for the quantification of enalapril, enalaprilat, carvedilol, O\u2010desmethyl carvedilol, 4\u2010 and 5\u2010hydroxyphenyl carvedilol as well as 3\u2010 and 8\u2010hydroxy carvedilol. To facilitate broader applications in adults, the elderly and children, a wide calibration range\u2014between 0.024\/0.049 and 50.000 ng\/ml\u2014was achieved with good linearity (<jats:italic>r<\/jats:italic> \u2265 0.995 for all analytes). In compliance with international bioanalytical guidelines, accuracy, precision, sensitivity and internal standard normalised matrix effects were further successfully validated with the exception of those for 3\u2010hydroxy carvedilol, which was therefore assessed semi\u2010quantitatively. Distinct haematocrits did not impact matrix effects or recoveries when analysing whole blood. Blood\u2010to\u2010plasma ratios were determined for all analytes to form the basis for pharmacokinetic modelling. Finally, incurred sample reanalysis of paediatric samples confirmed the reproducibility of the developed low\u2010volume LC\u2013MS\/MS method during study sample analysis. The assay facilitates the reliable generation of important data and contributes towards a safe drug therapy in children.<\/jats:p>","DOI":"10.1002\/dta.2949","type":"journal-article","created":{"date-parts":[[2020,10,30]],"date-time":"2020-10-30T17:16:44Z","timestamp":1604078204000},"page":"694-708","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Low\u2010volume LC\u2013MS\/MS method for the pharmacokinetic investigation of carvedilol, enalapril and their metabolites in whole blood and plasma: Application to a paediatric clinical trial"],"prefix":"10.1002","volume":"13","author":[{"given":"Tanja","family":"Gangnus","sequence":"first","affiliation":[{"name":"Institute of Clinical Pharmacy and Pharmacotherapy Heinrich Heine University  D\u00fcesseldorf Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1782-9937","authenticated-orcid":false,"given":"Bjoern 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