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. 2022 May 30;14(6):1163.
doi: 10.3390/pharmaceutics14061163.

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)

Affiliations

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)

Stephanie Laeer et al. Pharmaceutics. .

Abstract

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.

Keywords: ACEIs; congenital heart disease; dilated cardiomyopathy; enalapril; heart failure; orodispersible minitablets; pediatric cardiology.

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Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Figures

Figure 1
Figure 1
Enalapril (a,b) and enalaprilat (c,d) profiles of plasma concentrations over time with serum samples normalized by dose and bodyweight in steady state conditions in patients with heart failure due to dilated cardiomyopathy (a,c, n = 23) and congenital heart disease (b,d, n = 34) where profiles were measured under steady state conditions. Profiles were grouped according to age: Age group 1: 1 day to <1 year; Age group 2: 1 year to <6 years; age group 3: 6 years to <12 years.
Figure 2
Figure 2
Body weight normalized apparent oral clearance of Enalapril (ENA) as function of age in patients with heart failure due to dilated cardiomyopathy (DCM, open circles, n = 25) and due to congenital heart disease (CHD, closed circle, n = 61).

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