Fit-for-Purpose Quality Control System in Continuous Bioanalysis During Long-Term Pediatric Studies

Ali, Mohsin; Tins, Jutta; Burckhardt, Bjoern B.

doi:10.1208/s12248-019-0375-1

Cited by 7 publications

(4 citation statements)

References 20 publications

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“…In contrast to the bioanalysis of renin, the bioanalytical evaluation of the primary study endpoint (pharmacokinetics of the small molecule enalapril) was conducted using a chromatographic assay, which must comply with distinct international specification requirements than the ones for LBAs. Therefore, the recently published QC system on small molecules determined by mass spectrometry within the LENA project was not reasonable for the bioanalytical performance verification of the here presented humoral parameter renin by LBA [25]. Thus, a customized CMPV concept was designed addressing the special demands of a small-volume assay of endogenous renin by LBA within an academic environment.…”

Section: Discussionmentioning

confidence: 99%

A continued method performance monitoring approach for the determination of pediatric renin samples – application within a European clinical trial

Feickert

Burdman

Makowski

et al. 2020

Clinical Chemistry and Laboratory Medicine (CCLM)

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BackgroundPlasma renin levels were determined in the academia-driven, EU-funded “Labeling of Enalapril from Neonates up to Adolescents” (LENA) project to evaluate its role in pediatric heart failure. Quality-controlled bioanalysis is crucial to ensure reliable data generation. However, a comprehensive bioanalytical quality control (QC) concept to monitor the method performance within an academic environment was lacking.MethodsThus, a QC concept was designed encompassing regulatory guidance, international recommendations and current scientific discussions. The concept included (1) a system-suitability test, (2) verification of single bioanalytical runs by calibration curve performance and evaluation of QCs, (3) assessment of the inter-run accuracy according to Clinical Laboratory Standards Institute (CLSI) guideline, (4) monitoring of reproducibility by pediatric incurred samples, (5) blank-sample analysis and (6) participation in interlaboratory testing.ResultsThe concept was successfully applied to the academic project. About 11% of single runs were identified as invalid and triggered a re-analysis of unknown samples being included in those runs. The usefulness of the customized inter-run monitoring was demonstrated and proved the good accuracy from the first to the last run. All 147 reanalyzed incurred sample pairs complied with regulatory requirements.ConclusionsThe regulatory complied QC concept was customized for the demands of academia-driven pediatric trials and contributed to the reliable quantification of 965 pediatric renin samples.

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Section: Discussionmentioning

confidence: 99%

A continued method performance monitoring approach for the determination of pediatric renin samples – application within a European clinical trial

Feickert

Burdman

Makowski

et al. 2020

Clinical Chemistry and Laboratory Medicine (CCLM)

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“…More detailed information on this study is given in the Supporting Information. To continuously monitor the reproducibility of the assay during the analysis of study samples, ISR was applied based on previously established in‐house bioanalytical QC systems 31,32 . Following regulatory bioanalytical guidelines, reanalysis of 10% of the first 1,000 study samples with concentrations close to the maximum concentration ( c max ) and during the elimination phase is recommended 26,27 .…”

Section: Methodsmentioning

confidence: 99%

“…As part of in-house established comprehensive QC systems, 31,32 ISR was conducted for paediatric plasma samples to continuously monitor and verify the method performance after validation. Eight ISR pairs were randomly selected out of the total available plasma within a wide range for all analytes.…”

Section: Continued Methods Performance Verificationmentioning

confidence: 99%

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

Gangnus

Burckhardt

2020

Drug Testing and Analysis

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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.

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“…At the LLOQ, the mean accuracy ranged from 88.0% to 105.5%, 90.2% to 98.8% at the low concentration, 94.0% to 100.9% at the medium level, and 93.2% to 106.4% at the ULOQ. Study samples measured below the LLOQ were set to 0, and samples above the ULOQ were remeasured after dilution [51].…”

Section: Determination Of Enalapril and Enalaprilatmentioning

confidence: 99%

Enalapril and Enalaprilat Pharmacokinetics in Children with Heart Failure Due to Dilated Cardiomyopathy and Congestive Heart Failure after Administration of an Orodispersible Enalapril Minitablet (LENA-Studies)

et al. 2022

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Angiotensin-converting enzyme inhibitors (ACEI), such as enalapril, are a cornerstone of treatment for pediatric heart failure which is still used off-label. Using a novel age-appropriate formulation of enalapril orodispersible minitablets (ODMTs), phase II/III open-label, multicenter pharmacokinetic (PK) bridging studies were performed in pediatric patients with heart failure due to dilated cardiomyopathy (DCM) and congenital heart disease (CHD) in five participating European countries. Children were treated for 8 weeks with ODMTs according to an age-appropriate dosing schedule. The primary objective was to describe PK parameters (area under the curve (AUC), maximal concentration (Cmax), time to reach maximal concentration (t-max)) of enalapril and its active metabolite enalaprilat. Of 102 patients, 89 patients (n = 26, DCM; n = 63 CHD) were included in the primary PK endpoint analysis. Rate and extent of enalapril and its active metabolite enalaprilat were described and etiology and age could be identified as potential PK modifying factors. The dosing schedule appeared to be tolerated well and did not result in any significant drug-related serious adverse events. The PK analysis and the lack of severe safety events supports the applied age-appropriate dosing schedule for the enalapril ODMTs.

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Fit-for-Purpose Quality Control System in Continuous Bioanalysis During Long-Term Pediatric Studies

Cited by 7 publications

References 20 publications

A continued method performance monitoring approach for the determination of pediatric renin samples – application within a European clinical trial

A continued method performance monitoring approach for the determination of pediatric renin samples – application within a European clinical trial

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

Enalapril and Enalaprilat Pharmacokinetics in Children with Heart Failure Due to Dilated Cardiomyopathy and Congestive Heart Failure after Administration of an Orodispersible Enalapril Minitablet (LENA-Studies)

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