# Angiotensin II/Angiotensin I Ratio as a New Pharmacodynamic Parameter for Population Modelling in Healthy Adults and Children with Heart Failure Treated with Enalapril

## TL;DR

This study explores how enalapril affects heart failure patients, showing children may respond more strongly to the drug than adults.

## Contribution

The study introduces the angiotensin II/angiotensin I ratio as a new pharmacodynamic parameter for modeling enalapril effects in children and adults.

## Key findings

- Children with heart failure showed higher baseline angiotensin II/angiotensin I ratio than healthy adults.
- Enalaprilat in children achieved significant inhibition of the angiotensin II/angiotensin I ratio within four hours.
- Children with heart failure appear more sensitive to enalaprilat compared to healthy adults.

## Abstract

Background/Objectives: Since 2023, enalapril orodispersible minitablets have been approved in Europe for paediatric heart failure from birth, but no population pharmacodynamic analyses have yet been conducted in this patient group. The objectives were to investigate the effect of the active metabolite enalaprilat on the angiotensin II/angiotensin I ratio in children with heart failure and to determine potential differences compared to healthy adults. Methods: Population pharmacokinetic/pharmacodynamic analysis for healthy adults and population pharmacodynamic analysis for children with heart failure were performed using Monolix. Data were analyzed from 9 healthy adults after a single dose of enalapril and from 27 angiotensin-converting enzyme (ACE) inhibitor-naïve children with heart failure treated with enalapril orodispersible minitablets for up to one year in the ‘Labeling of Enalapril from Neonates up to Adolescents’ (LENA) studies. Results: For the relationship between enalaprilat and the angiotensin II/angiotensin I ratio, a maximum inhibition (Imax) model with full inhibition and sigmoidicity factor was selected for healthy adults and without sigmoidicity factor for children with heart failure. In children with heart failure, the population estimate for the baseline effect was higher (0.19 versus 0.043) and for the half-maximal inhibitory concentration lower (1.19 µg/L versus 30.01 µg/L) than in healthy adults. Four hours after a median initial dose of 0.06 mg/kg enalapril maleate, the angiotensin II/angiotensin I ratio decreased by a median of 79.3% in children with heart failure. Conclusions: Effective ACE inhibition can be assumed at the administered dose in children with heart failure. Population analyses suggest that children with heart failure may be more sensitive to enalaprilat than healthy adults.