Abstract 4141312: Safe Initial Dosing of Innovative Enalapril Orodispersible Minitablets in Newly Treated Newborns, Infants and Young Children with Heart Failure – Results of a Population Pharmacokinetic Analysis of the LENA Trials

Background: Safe dosing in children with heart failure requires consideration of clinically relevant covariates. In the European project Labeling of Enalapril from Neonates up to Adolescents (LENA), heart failure was treated with innovative enalapril orodispersible minitablets (ODMT) using an age- and weight-dependent dosing regimen. Research Question: Does the population pharmacokinetic analysis of the LENA data reveal relevant clinical covariates in dosing besides age and weight for newborns, infants and young children newly treated with enalapril ODMT? Methods: We analyzed data of ACE inhibitor naïve subjects with heart failure due to congenital heart disease (n=31) or dilated cardiomyopathy (n=3) from the prospective, open-label, multicenter phase II/III pharmacokinetic bridging studies using NONMEM ® . Allometric scaling was applied to the clearance (CL/F) and volume of distribution (V d /F) of enalapril and enalaprilat. The covariates age, sex, serum creatinine and Ross score were tested using stepwise covariate modeling. Simulations were conducted to assess the effects of the identified covariates. Results: In total, 173 enalapril and 268 enalaprilat serum concentrations from 34 subjects (25 days–2.1 years, median age=0.3 years) were included in the analysis. A combined model with a one compartment model of enalapril coupled with a one compartment model of enalaprilat with absorption lag was chosen as the structural model. The population estimates were 4.98 L (V d /F of enalapril), 34.1 L (V d /F of enalaprilat), 4.61 L/h (CL/F of enalapril) and 1.55 L/h (CL/F of enalaprilat). For enalaprilat, part of the variance in CL/F could be explained by age and serum creatinine, while part of the variance in V d /F could be explained by the Ross score. The simulations indicated that age, weight, and serum creatinine values above the normal reference range are clinically relevant covariates for the initial dose and the dose at steady state, while the Ross score is a relevant covariate for the initial dose. An increase in the Ross score by one point leads to an average increase in the initial maximum concentration of enalaprilat of 24% in the examined Ross score range from 0 to 11. Conclusion: The newly detected covariate Ross score provides the scientific basis for considering the severity of heart failure at the initial dose. The initial dose should be lowered depending on the level of the Ross score to avoid high peak concentrations and a potential drop in blood pressure.