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

Abstract

Evidence‐based pharmacotherapy with carvedilol and enalapril in children suffering from heart failure is insufficient owing to limited pharmacokinetic data. 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‐based pharmacotherapy. Considering ethical paediatric constraints, a low‐volume liquid chromatography coupled to mass spectrometry (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‐hydroxy carvedilol. To facilitate broader applications in adults, the elderly and children, a wide calibration range—between 0.024/0.049 and 50.000 ng/ml—was achieved with good linearity (r ≥ 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‐hydroxy carvedilol, which was therefore assessed semi‐quantitatively. Distinct haematocrits did not impact matrix effects or recoveries when analysing whole blood. Blood‐to‐plasma 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‐volume LC–MS/MS method during study sample analysis. The assay facilitates the reliable generation of important data and contributes towards a safe drug therapy in children.

Insights and perspectives into clinical biomarker discovery in pediatric heart failure and congenital heart disease—a narrative review

“…Metabolomic studies, including those in adult HF (2,80), are a way of highlighting biochemical pathways and signatures correlated to the underlying pathophysiology that may aid in the diagnosis or management of pediatric HF and CHD (81,82). A wide range of metabolites in a variety of CHDs have been reported (83)(84)(85), notably acylcarnitines, triacylglycerides, amino-acid related compounds, lipids, and free fatty acids.…”

Spectrophotometric Estimation of Carvedilol via Schiff̕ s base Reaction with 4-Hydroxybenzaldehyde

“…Various methods were applied for the estimation of CARVL. The most accurate methods include high performance liquid chromatography [3-8], HPLC/MS [9],UHPLC [10],LC/MS/MS [11] nanosensor probe [12], electrochemical sensor [13], voltammetric determination [14], spectrofluorimetry in presence of atenolol [15] and SPE-spectrofluorimetric [16].…”