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Background <p>Enalapril orodispersible minitablets (ODMT) have been authorised by the European Medicines Agency for the treatment of heart failure in children from birth to 17 years of age in 2023. Consequently, the use of enalapril in very young and angiotensin-converting enzyme inhibitor (ACEi) naïve patients is expected to increase.</p> Objectives <p>Simultaneous characterisation of the pharmacokinetics (PK) of enalapril and the active metabolite enalaprilat in ACEi naïve children with heart failure using a combined population pharmacokinetic (PopPK) model and identification of clinically relevant covariates for the dosing of enalapril in this population.</p> Methods <p>Data of ACEi naïve subjects from the European project ‘Labeling of Enalapril from Neonates up to Adolescents’ (LENA) were analysed using nonlinear mixed effects modelling. In the prospective, open-label, multicentre phase II/III PK bridging studies, children with heart failure due to dilated cardiomyopathy (DCM) and congenital heart disease (CHD) received enalapril ODMT according to an age- and weight-dependent dosing regimen. Allometric scaling was implemented for the disposition parameters of enalapril and enalaprilat. Stepwise covariate modelling was used to test the covariates age, sex, serum creatinine and Ross score. The final model was validated using nonparametric bootstrap analysis. Simulations were performed to assess the impact of the covariates after the first dose and at steady state.</p> Results <p>The analysed dataset comprised 173 enalapril and 268 enalaprilat serum concentrations from 34 subjects aged 25 days to 2.1 years (median age = 0.3 years). A combined model consisting of a one-compartment model for enalapril coupled with a one-compartment model for enalaprilat with absorption lag was selected as the structural model. Covariate analysis revealed that the weight-adjusted apparent clearance of enalaprilat increases with increasing age and decreases with increasing serum creatinine. In addition, the weight-adjusted apparent volume of distribution of enalaprilat decreases with increasing Ross score. The simulations indicated that serum creatinine levels above the normal reference range, age and weight were clinically relevant covariates for both the first dose and the steady state dose of enalapril. Furthermore, the simulations indicated that the Ross score is a clinically relevant covariate for the first dose of enalapril.</p> Conclusions <p>The results of the PopPK analysis and simulations indicated that, in addition to the currently considered parameters of weight and renal function, the parameters of age and severity of heart failure should also be considered when dosing enalapril in children with heart failure.</p> Trial Registration <p>Trial registration number (date of registration): EudraCT 2015-002335-17 (30 November 2015), EudraCT 2015-002396-18 (30 November 2015). The trials were registered on the EU Clinical Trials Register (<a href="https://www.clinicaltrialsregister.eu">https://www.clinicaltrialsregister.eu</a>).</p>

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Population Pharmacokinetic Analysis of Enalapril and Enalaprilat in Newly Treated Children with Heart Failure: Implications for Safe Dosing of Enalapril (LENA Studies)

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  • 发表日期：

    2025年6月3日

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  • Melina Steichert,
  • Willi Cawello,
  • Stephanie Laeer,
  • Jörg Breitkreutz,
  • Ingrid Klingmann,
  • Florian Lagler,
  • Jan de Hoon,
  • Michiel Dalinghaus,
  • Milica Bajcetic,
  • Saskia N. de Wildt,
  • Anne Keatley-Clarke,
  • Johannes M. P. J. Breur,
  • Christoph Male,
  • Laszlo Ablonczy,
  • Thomas Mir,
  • Vladislav Vukomanovic,
  • Milan Dukic,
  • Ida Jovanovic,
  • Bjoern B. Burckhardt,
  • Karl Kleine,
  • Angelika Moder,
  • Emina Obarcanin,
  • Peter Wagner,
  • Jennifer Walsh,
  • Anne van Hecken,
  • Lucie Spatenkova,
  • Mohsin Ali,
  • Bojana Božić,
  • Maja Bijelić,
  • Ilja Burdman,
  • Agnes Ciplea,
  • Muhammed Faisal,
  • Samieh Farahani,
  • Martin Feickert,
  • Tanja Gangnus,
  • Milica Lazic,
  • Nina Makowski,
  • Fabian Süssenbach,
  • Marijke van der Meulen,
  • Saša Popović,
  • Miro Parezanović,
  • Nori Smeets,
  • Vanessa Swoboda,
  • Dragana Bojanin,
  • Stefan Đorđević,
  • Jasminka Dragić,
  • Ann-Kathrin Holle,
  • Bosiljka Jovičić,
  • Jovan Košutić,
  • Gordana Kozomara,
  • Haidara Majid,
  • Jadranka Mitrović,
  • Sanja Ninić,
  • Miro Parezanovic,
  • Vojislav Parezanovic,
  • Andrija Pavlović,
  • Sergej Prijić,
  • Branislava Rebić,
  • Igor Stefanović,
  • Daniel Tordas,
  • Irena Vulićević,
  • Anke Bartel,
  • Andjelka Čeko,
  • Marissa Herborts,
  • Annelies Hennink,
  • Bosiljka Kosanović,
  • Sanja Kostic,
  • Ljiljana Isailović,
  • Jasmina Maksimovic,
  • Badies Manai,
  • Nada Martinović,
  • Gyöngyi Máté,
  • Miloš Perišić,
  • Jelena Reljić,
  • Regina Pirker,
  • Marta Salamomovic,
  • Claudia Schlesner,
  • Jutta Tins,
  • Eva Wissmann

摘要

Background

Enalapril orodispersible minitablets (ODMT) have been authorised by the European Medicines Agency for the treatment of heart failure in children from birth to 17 years of age in 2023. Consequently, the use of enalapril in very young and angiotensin-converting enzyme inhibitor (ACEi) naïve patients is expected to increase.

Objectives

Simultaneous characterisation of the pharmacokinetics (PK) of enalapril and the active metabolite enalaprilat in ACEi naïve children with heart failure using a combined population pharmacokinetic (PopPK) model and identification of clinically relevant covariates for the dosing of enalapril in this population.

Methods

Data of ACEi naïve subjects from the European project ‘Labeling of Enalapril from Neonates up to Adolescents’ (LENA) were analysed using nonlinear mixed effects modelling. In the prospective, open-label, multicentre phase II/III PK bridging studies, children with heart failure due to dilated cardiomyopathy (DCM) and congenital heart disease (CHD) received enalapril ODMT according to an age- and weight-dependent dosing regimen. Allometric scaling was implemented for the disposition parameters of enalapril and enalaprilat. Stepwise covariate modelling was used to test the covariates age, sex, serum creatinine and Ross score. The final model was validated using nonparametric bootstrap analysis. Simulations were performed to assess the impact of the covariates after the first dose and at steady state.

Results

The analysed dataset comprised 173 enalapril and 268 enalaprilat serum concentrations from 34 subjects aged 25 days to 2.1 years (median age = 0.3 years). A combined model consisting of a one-compartment model for enalapril coupled with a one-compartment model for enalaprilat with absorption lag was selected as the structural model. Covariate analysis revealed that the weight-adjusted apparent clearance of enalaprilat increases with increasing age and decreases with increasing serum creatinine. In addition, the weight-adjusted apparent volume of distribution of enalaprilat decreases with increasing Ross score. The simulations indicated that serum creatinine levels above the normal reference range, age and weight were clinically relevant covariates for both the first dose and the steady state dose of enalapril. Furthermore, the simulations indicated that the Ross score is a clinically relevant covariate for the first dose of enalapril.

Conclusions

The results of the PopPK analysis and simulations indicated that, in addition to the currently considered parameters of weight and renal function, the parameters of age and severity of heart failure should also be considered when dosing enalapril in children with heart failure.

Trial Registration

Trial registration number (date of registration): EudraCT 2015-002335-17 (30 November 2015), EudraCT 2015-002396-18 (30 November 2015). The trials were registered on the EU Clinical Trials Register (https://www.clinicaltrialsregister.eu).