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

Abstract

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 ).

Fig. 1

Observed concentration of enalapril (a) and enalaprilat (b) plotted against time since last dose on a linear scale. The inset plots show the data on a logarithmic–linear scale. The dashed line indicates the lower limit of quantification. Observations above the lower limit of quantification are shown as black circles and observations below the lower limit of quantification are shown as red circles. Darker circles indicate overlapping observations

Fig. 2

Schematic illustration of the final structural model. The box on the right contains the underlying equations for the transfer rate constants. CL_ENA/F apparent clearance of enalapril, CL_ENAAT/F apparent clearance of enalaprilat, f_m fraction of enalapril metabolised (fixed to 0.7), k₂₀ transfer rate constant (first-order) from the central compartment of enalapril to the urine, k₂₃ transfer rate constant (first-order) from the central compartment of enalapril to the central compartment of enalaprilat, k₃₀ transfer rate constant (first-order) from the central compartment of enalaprilat to the urine, k_a absorption rate constant (fixed to 0.6 1/h), t_lag lag time, V_d_ENA/F apparent volume of distribution of enalapril, V_d_ENAAT/F apparent volume of distribution of enalaprilat

Fig. 3

Goodness-of-fit plots for the final model of enalapril (a) and enalaprilat (b). For (a) and (b), the red dashed line is the line of unity (top left and top right), the median of the conditional weighted residuals (bottom left) or the reference line of zero (bottom right). Darker circles indicate overlapping observations

Fig. 4

Prediction- and variability-corrected visual predictive checks of enalapril and enalaprilat for the final model. Observations are shown as circles. Darker circles indicate overlapping observations. The solid line represents the median of the observations. The dashed lines are the 2.5th and 97.5th percentiles of the observations. The shaded areas represent the 95% confidence intervals of the median (grey) and the 2.5th and 97.5th percentiles (blue) predicted by the model

Fig. 5

Impact of weight and statistically significant covariates included in the final model on the predicted pharmacokinetic parameters of enalaprilat after the first dose (AUC_∞, C_max,1) and at steady state (AUC_τ, C_max,ss). The predicted AUC_∞, AUC_τ, C_max,1 and C_max,ss at the given weight and covariate values (5th, 25th, 75th and 95th percentiles of the analysed population) were compared with those predicted for a reference subject with a weight of 5 kg, an age of 0.34 years, a Ross score of 4 and a serum creatinine of 23.37 µmol/L. The black dots and error bars show the median of the ratio to reference with a 90% confidence interval (n = 988). The grey area shows the 80–125% range in relation to the reference, whereby the selected range is based on the standard bioequivalence limits. AUC_∞ area under the concentration–time curve from time zero to infinity, AUC_τ area under the concentration–time curve during a dosage interval, C_max,1 maximum serum drug concentration after the first dose, C_max,ss maximum steady state serum drug concentration during a dosage interval

Fig. 6

Impact of the Ross score on the maximum serum drug concentration after the first dose (C_max,1) of enalaprilat after administration of 0.25 mg enalapril maleate. The boxplot shows the predicted C_max,1 for subjects with a weight of 5 kg, an age of 0.34 years, a serum creatinine of 23.37 µmol/L and a Ross score between 0 and 11 (minimum to maximum Ross score of the analysed population). For each Ross score, 988 C_max,1 values were estimated. The upper whisker extends from the 75th percentile to the largest value no further than 1.5 times the interquartile range from the 75th percentile. The lower whisker extends from the 25th percentile to the smallest value no further than 1.5 times the interquartile range from the 25th percentile. Data beyond the end of the whiskers are outliers and are shown as black dots. C_max,1 maximum serum drug concentration after the first dose