Sample Preparation and Extraction in Small Sample Volumes Suitable for Pediatric Clinical Studies: Challenges, Advances, and Experiences of a Bioanalytical HPLC-MS/MS Method Validation Using Enalapril and Enalaprilat

Burckhardt, Bjoern B.; Laeer, Stephanie

doi:10.1155/2015/796249

Cited by 10 publications

(11 citation statements)

References 14 publications

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“…The applied liquid chromatography-tandem mass spectrometry methods were accurate, precise, and not affected by a matrix effect. 24 A recent publication using a comparable study design and method of detection to this study demonstrated maximum plasma concentrations of enalapril and enalaprilat, following 10 mg of a standard enalapril tablet, to be 58 ng/mL and 41 ng/mL, which are similar to 61 ng/mL and 48 ng/mL in this study. 23 Time to maximum concentration and AUC 0-Ý were also similar.…”

Section: Discussionsupporting

confidence: 80%

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Relative Bioavailability of Enalapril Administered as Orodispersible Minitablets in Healthy Adults

Hecken

Burckhardt

Khalil

et al. 2019

Clinical Pharm in Drug Dev

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The angiotensin-converting enzyme inhibitor enalapril is commonly used to treat chronic heart failure in children.Because some children are unable to swallow capsules or tablets, a new, age-appropriate, orodispersible minitablet (ODMT) containing 1 mg of enalapril was developed within the EU-funded LENA (Labeling of Enalapril from Neonates up to Adolescents) consortium. In order to support the clinical evaluation of this new formulation in children, a relative bioavailability study was performed in healthy adults, comparing the bioavailability of enalapril in the ODMT with that of a reference product (RP) Renitec, a registered standard enalapril tablet formulation. In this open-label, randomized 3-way crossover study, 24 healthy subjects received a 10-mg enalapril dose administered as (1) 2 × 5-mg tablets of the RP swallowed with water, (2) 10 × 1-mg ODMT swallowed with water, and (3) 10 × 1 mg ODMT dispersed on the tongue. When the relative bioavailability of the ODMT formulation swallowed with water was compared with that of the RP, the estimated 90%CIs for the ratio of area under the concentration-time curve (AUC 0-Ý ) and or peak concentration (C max ) of enalapril were 92.34% to 106.49% and 91.28% to 115.72%, respectively, which are within the accepted bioequivalence limits of 80% to 125%. Following dispersion of the ODMT in the mouth, a slightly higher C max for enalapril was observed as compared with the RP with an upper 90%CI of 127.57%, slightly exceeding the bioequivalence limit. Taken together, it was demonstrated that the method of administration of the ODMT, swallowed or dispersed, did not significantly affect the bioavailability of enalapril.

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Section: Discussionsupporting

confidence: 80%

“…However, all drug concentrations in the presented study were determined by a validated bioanalytical assay in compliance with EMA and US FDA guidance on bioanalytical method validation. The applied liquid chromatography‐tandem mass spectrometry methods were accurate, precise, and not affected by a matrix effect …”

Section: Discussionmentioning

confidence: 99%

Relative Bioavailability of Enalapril Administered as Orodispersible Minitablets in Healthy Adults

Hecken

Burckhardt

Khalil

et al. 2019

Clinical Pharm in Drug Dev

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“…Determinations for enalapril, enalaprilat, aldosterone, renin, plasma renin activity and angiotensin I were performed at the institute or by an external partner (Spranger Laboratories, Ingolstadt, Germany). Drug concentrations of enalapril and its metabolite (enlaprilat) were determined using a low-volume LC/MS-MS method [ 21 ], whereas humoral parameters (aldosterone, renin, plasma renin activity and angiotensin I) were determined using enzyme-linked immunosorbent assays (ELISA) [ 22 , 23 ] or radioimmunoassays (RIA). The bioanalysis at the laboratories was performed blinded.…”

Section: Methodsmentioning

confidence: 99%

A feasibility study prior to an international multicentre paediatric study to assess pharmacokinetic/pharmacodynamic sampling and sample preparation procedures, logistics and bioanalysis

Ciplea¹,

Laeer²,

Burckhardt³

2018

Contemporary Clinical Trials Communications

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BackgroundVariability in pre-analytical procedures such as blood sampling, sample preparation and transport can substantially influence bioanalytical results and subsequently impair reliability of data gathered during clinical trials. Especially in vulnerable populations, all efforts should be made to facilitate high-quality data extraction excluding unnecessary or repeated intervention.MethodsThe EU-funded LENA project (Labeling of Enalapril from Neonates up to Adolescents) included a feasibility study in its preparatory procedures prior to first-in-child studies. Derived from a regular study visit, it encompassed all procedures, from sampling of two study-specific drugs and four sensitive humoral parameters to bioanalysis, to evaluate the quality of obtained samples and applicability of logistical and bioanalytical procedures. Drug administration to healthy adults was circumvented by pre-spiking the blood collection tubes with a drug solution. Five clinical sites were evaluated.ResultsClinical teams' preparedness and applicability of required sampling procedures was investigated in 18 volunteers, on-site. 97% of collected pharmacokinetic (PK) samples and 93% of samples for humoral parameters were obtained eligibly. Results met expectations, though one team had to be re-trained and performed a re-run. Planned procedures for sampling, sample preparation, transport and analysis were found to be suitable for being applied within paediatric trials.ConclusionThe concept of the presented feasibility study that simultaneously assesses PK/PD sampling, sample preparation, logistics and bioanalysis proved to be a promising tool for trial preparation. It revealed improperly installed processes and bottlenecks that required adjustments prior to start of recruitment. It facilitated high-quality conduct from the first moment of paediatric pivotal studies.

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“…The use of liquid chromatography coupled to mass spectrometry (LC–MS/MS) offers a tool to quantify sensitively and targeted drugs and metabolites. Even if LC–MS/MS methods suitable for the detection of enalapril, enalaprilat and carvedilol have been developed for paediatric demands, 23,24 to our knowledge, no bioanalytical method is available to simultaneously assess enalapril, carvedilol and their metabolites. However, this is paramount to ensure safe and evidence‐based pharmacotherapy in children suffering from heart failure.…”

Section: Introductionmentioning

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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Sample Preparation and Extraction in Small Sample Volumes Suitable for Pediatric Clinical Studies: Challenges, Advances, and Experiences of a Bioanalytical HPLC-MS/MS Method Validation Using Enalapril and Enalaprilat

Cited by 10 publications

References 14 publications

Relative Bioavailability of Enalapril Administered as Orodispersible Minitablets in Healthy Adults

Relative Bioavailability of Enalapril Administered as Orodispersible Minitablets in Healthy Adults

A feasibility study prior to an international multicentre paediatric study to assess pharmacokinetic/pharmacodynamic sampling and sample preparation procedures, logistics and bioanalysis

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

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