Low ‐volume LC‐MS/MS method for the pharmacokinetic investigation of carvedilol, enalapril and their metabolites in whole blood and plasma: application to a paediatric clinical trial

AbstractEvidence ‐based pharmacotherapy with carvedilol and enalapril in children suffering from heart failure is insufficient owing to limited pharmacokinetic data.1 While a few datasets regarding enalapril, its metabolite enalaprilat and carvedilol in children have been published, pharmacokinetic data on carvedilol metabolites is 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 ‐based pharmacotherapy. Considering ethical paediatric constraints, a low‐volume LC‐MS/MS assay was developed using whole blood or plasma for the quantification of enalapril, enalaprilat, carvedilol, O‐desmethyl carvedilol, 4‐ and 5‐hydroxyphenyl carvedilol as well as 3‐ and 8‐hydrox y carvedilol. To facilitate broader applications in adults, the elderly and children, a wide calibration range ‐ between 0.024/0.049 ng/mL and 50.000 ng/mL ‐ was achieved with good linearity (r≥0.995 for all analytes). In compliance with international bioanalytical guidelines, accuracy, precis ion, sensitivity, and internal standard normalised matrix effects were further successfully validated with the exception of those for 3‐hydroxy carvedilol, which was therefore assessed semi‐quantitatively. Distinct haematocrits did not impact matrix effe...
Source: Drug Testing and Analysis - Category: Drugs & Pharmacology Authors: Tags: RESEARCH ARTICLE Source Type: research