Enalapril orodispersible minitablets for pediatric heart failure - a population pharmacokinetic analysis from multicenter Phase II/III LENA clinical trials
Muhammad Faisal (1), Melina Steichert (1), Willi Cawello (1), Stephanie Laeer (1) and the LENA consortium
(1) Institute of Clinical Pharmacy and Pharmacotherapy, Heinrich-Heine-University Düsseldorf, Germany
Introduction: Enalapril is an angiotensin-converting enzyme inhibitor (ACEI) and is widely used in the treatment of pediatric heart failure without an approved treatment and dosage formulation for children below 20 kg of body weight in Europe [1]. This is regarded as a severe risk for children as pediatric heart failure is characterized by high mortality rates [2]. Previously conducted non-compartment pharmacokinetic analysis revealed potential influence of age and etiology of heart failure such as dilated cardiomyopathy (DCM) or congenital heart disease (CHD) on enalapril and enalaprilat pharmacokinetics in the pediatric patients [3, 4].
Objectives:
1) To develop a combined population pharmacokinetic (POP-PK) model to simultaneously predict the pharmacokinetics of enalapril and its active metabolite enalaprilat in pediatric heart failure patients and to evaluate appropriate covariate model in this population.
2) To perform simulations using the age-appropriate dosing scheme to compare the exposure of enalapril and enalaprilat in pediatric patients vs. healthy adults.
Methods: In the two LENA Phase II/III prospective, open-labeled, multicenter clinical trials, pharmacokinetic bridging and safety studies were conducted where pediatric patients of age 1 day to below 12 years were treated with the age-specific dosing regimen of enalapril administered using the newly developed orodispersible minitablets. The age and weight based dosing scheme was previously predicted using the physiological based pharmacokinetic (PBPK) approach and simulated similar exposures of the active ACEI enalaprilat in pediatric age groups compared to healthy adults [4].
The POP-PK model was developed using the NONMEM software version 7.4.0. The general linear model was developed using the ADVAN7 subroutine with the TRANS1 parametrization subroutine. Post-modeling processes including model diagnostics, data management, and graphical evaluations were performed using R software 4.1.0.
A combined model was developed for enalapril and enalaprilat using differential equations to simultaneously account for the pharmacokinetics of enalapril and enalaprilat. Both one and two-compartment models were tested for enalapril and its active metabolite enalaprilat. Allometric scaling and maturation functions were tested to account for the effect of maturating organ functions on model parameters. Covariate analysis was performed using the stepwise covariate modeling approach using the Perl-speaks-NONMEM version 5.2.6. The effect of demographic covariates like age, body weight, height, and sex as well as the effect of etiology of heart failure, treatment status, and kidney function on the model parameters was searched. The model was validated using the visual predicted check plots and bootstrap analysis. Simulations were then performed to simulate the concentrations and exposures of enalapril and enalaprilat in neonates up to adolescents.
Results: The population analysis was based on 916 enalapril and 917 enalaprilat measurements from 101 subjects (70 with CHD and 31 with DCM).The combined model with one-compartment model of enalapril coupled with one-compartment of enalaprilat was selected based on the significance criteria. Allometric scaling applied on the volume of distribution (V/f) and clearance (CL/f) parameters along with the maturation functions applied on CL/f parameters significantly accounted for the maturation of age-related elimination pathways. The population estimates were 79.1 L (V/f of enalapril), 605 L (V/f of enalaprilat), 84.3 mL/min (CL/f of enalapril) and 17.5 mL/min (CL/f of enalaprilat). In the forward stepwise covariate search, a significant effect of etiology of heart failure on the enalapril CL/f was identified; however, this relationship was not significant in the backward elimination step. All other tested covariate relationships were insignificant. The simulations using the age appropriate dosing scheme showed similar exposures of the active metabolite enalaprilat in all pediatric age groups compared to the exposures in adults.
Conclusions: POP-PK modeling analysis successfully predicted the pharmacokinetics of enalapril and enalaprilat in pediatric patients from 1 day to below 12 years of age. Age was the dominating covariate factor to explain enalapril and enalaprilat exposures in this population. Finally, enalapril should be used according to the PBPK model-based age-appropriate dosing scheme for children with heart failure [4, 5].
References:
[1] EMA. Committee for Proprietary Medicinal Products (CPMP) Summary Information of Referral Opinion Pursuant to Article 30 of Council Directive 2001/83/EC for Renitec and associated names (See Annex I). 04 December 2003. https://www.ema.europa.eu/documents/referral/summary-information-referral-opinion-pursuant-article-30-council-directive-2001/83/ec-renitec-associated-names-see-annex-i-international-non-proprietary-name-inn-enalapril-background_en.pdf. Accessed 8 Mar 2023.
[2] Webster G, Zhang J, Rosenthal D. Comparison of the epidemiology and co-morbidities of heart failure in the pediatric and adult populations: a retrospective, cross-sectional study. BMC Cardiovasc Disord. 2006;6:23.
[3] Faisal M, Cawello W, Laeer S. Clinical Pharmacokinetics of Enalapril and Enalaprilat in Pediatric Patients-A Systematic Review. Front Pediatr. 2021;9:611322.
[4] Laeer S, Cawello W, Burckhardt BB, Ablonczy L, Bajcetic M, Breur JMPJ, et al. 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). Pharmaceutics 2022;14:1163
[5] Bajcetic M, Wildt SN de, Dalinghaus M, Breitkreutz J, Klingmann I, Lagler FB, et al. Orodispersible minitablets of enalapril for use in children with heart failure (LENA): Rationale and protocol for a multicentre pharmacokinetic bridging study and follow-up safety study. Contemp Clin Trials Commun. 2019;15:100393.