Extrapolation of enalapril efficacy from adults to children using pharmacokinetic/pharmacodynamic modelling

Kechagia, Irene-Ariadne; Kalantzi, Lida; Dokoumetzidis, Aristides

doi:10.1111/jphp.12471

Cited by 7 publications

(7 citation statements)

References 10 publications

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“…The value of the total rate constant of enalapril elimination through renal and metabolic route was estimated to be 0.93 1/h and was in line to the reported value of 0.94 1/h (36). The value of the rate constant of metabolite formation (KM) estimated using transit compartment model was 0.69 1/h and was in line to the reported value of 0.9 1/h estimated using the LAG time model (7). The estimated value of the rate constant of enalaprilat elimination was 0.175 1/h and was in line to the reported value of 0.14 1/h (36).…”

Section: Discussionsupporting

confidence: 86%

“…The one compartment model was also not able to predict the bi-exponential elimination phase of the metabolite. The two-compartment population pharmacokinetic model with proportional residual error model has been reported in the literature to model enalaprilat concentrations, however, a combined additive plus proportional residual error model significantly dropped the objective function and was used in our final base model (7). A three-compartment model was also tested but resulted in higher standard errors with no significant change in the objective function and was rejected.…”

Section: Discussionmentioning

confidence: 99%

“…Enalapril has been recommended for the treatment of adult heart failure (7) and has been shown to prolong the survival rates in CHF patients (8). Around 60% of the administered oral dose of the drug is absorbed through the gastrointestinal tract.…”

Section: Introductionmentioning

confidence: 99%

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Simultaneous Semi-Mechanistic Population Pharmacokinetic Modeling Analysis of Enalapril and Enalaprilat Serum and Urine Concentrations From Child Appropriate Orodispersible Minitablets

et al. 2019

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Enalapril is recommended as the first line of therapy and is proven to improve survival rates for treatment of Pediatric Heart Failure; however, an approved drug and child appropriate dosage formulation is still absent. The present analysis was conducted to perform a detailed model informed population pharmacokinetic analysis of prodrug enalapril and its active metabolite enalaprilat in serum and urine. Further, a model informed dosage form population-pharmacokinetic analysis was conducted to evaluate differences in pharmacokinetics of enalapril and its active metabolite enalaprilat when prodrug was administered to 24 healthy adults in a crossover, two periods, two treatments, phase I clinical trial using child-appropriate orodispersible mini-tablets (ODMT) and reference (Renitec®) dosage formulation. A simultaneous semi-mechanistic population-pharmacokinetic model was developed using NONMEM software, which predicted full profile serum and urine concentrations of enalapril and enalaprilat. First-order conditional estimation with interaction was used for parameter estimation. Transit compartments added using Erlang distribution method to predicted enalapril absorption and enalaprilat formation phases. Normalized body weight was identified as covariate related to enalapril volume of distribution. Visual predictive check (VPC) plots and conducted bootstrap analysis validated the model. The data from the two formulations were pooled for population-pharmacokinetic analysis and covariate effect of the formulation was found on mean transit time (MTT1) of enalapril absorption. In addition, data of each formulation were modeled separately and the estimated parameters of each individual administered both formulations were correlated using paired samples Wilcoxon rank test ( p < 0.05 = significant) which also showed only a significant difference ( p = 0.03) in MTT1 i.e., 5 min early appearance of enalapril from ODMT compared to reference tablets. No difference in the pharmacokinetics of active enalaprilat was found from the ODMT compared to the reference formulation. The population pharmacokinetic analysis provided detailed information about the pharmacokinetics of enalapril and enalaprilat, which showed that the ODMT formulation might have similar pharmacodynamic response compared to the reference formulation.

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Section: Discussionsupporting

confidence: 86%

Section: Discussionmentioning

confidence: 99%

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Simultaneous Semi-Mechanistic Population Pharmacokinetic Modeling Analysis of Enalapril and Enalaprilat Serum and Urine Concentrations From Child Appropriate Orodispersible Minitablets

et al. 2019

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“…107, 111 Drug trials in pediatric cardiomyopathy are challenging because of limitations in power due to small sample size, lack of validated endpoints, and incomplete pharmacokinetic/pharmacodynamic data. 110, 112, 113 A current study of sacubitril/valsartan in children is using a novel global rank endpoint as the primary outcome. 114 If successful, this may prove to be a useful endpoint the design of future studies.…”

Section: Dilated Cardiomyopathymentioning

confidence: 99%

Pediatric Cardiomyopathies

Lee

Hsu

Kantor

et al. 2017

Circulation Research

246

218

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Pediatric cardiomyopathies are rare diseases with an annual incidence of 1.1–1.5 per 100,000. Dilated and hypertrophic cardiomyopathies are the most common; restrictive, noncompaction, and mixed cardiomyopathies occur infrequently; and arrhythmogenic right ventricular cardiomyopathy is rare. Pediatric cardiomyopathies can result from coronary artery abnormalities, tachyarrhythmias, exposure to infection or toxins, or secondary to other underlying disorders. Increasingly, the importance of genetic mutations in the pathogenesis of isolated or syndromic pediatric cardiomyopathies is becoming apparent. Pediatric cardiomyopathies often occur in the absence of co-morbidities such as atherosclerosis, hypertension, renal dysfunction, and diabetes; as a result, they offer insights into the primary pathogenesis of myocardial dysfunction. Large international registries have characterized the epidemiology, etiology, and outcomes of pediatric cardiomyopathies. Although adult and pediatric cardiomyopathies have similar morphologic and clinical manifestations, their outcomes differ significantly. Within two years of presentation, normalization of function occurs in 20% of children with dilated cardiomyopathy, and 40% die or undergo transplantation. Infants with hypertrophic cardiomyopathy have a two-year mortality of 30%, whereas death is rare in older children. Sudden death is rare. Molecular evidence indicates that gene expression differs between adult and pediatric cardiomyopathies, suggesting treatment response may differ as well. Clinical trials to support evidence-based treatments and the development of disease-specific therapies for pediatric cardiomyopathies are in their infancy. This compendium summarizes current knowledge of the genetic and molecular origins, clinical course, and outcomes of the most common phenotypic presentations of pediatric cardiomyopathies, and highlights key areas where additional research is required.

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“…To date, limitations in data generation are being addressed by increased acceptance of extrapolation methodologies, 42,43 in which pharmacokinetics, pharmacodynamics and efficacy are inferred from a reference patient population, and eventually from animals, another compound or disease. [44][45][46] Whereas inferential methods are extremely important, and formal extrapolation approaches provides transparency for empirical dose selection, which is often observed during off-label use of a medicinal product, a key issue remains, in that any data oncoming from the target population is likely to be sparse and need to be integrated with existing knowledge, whether or not previously framed under an extrapolation exercise. It is therefore essential to maximise the usefulness of the data obtained with the minimum number of subjects enrolled.…”

Section: Accepted Manuscriptmentioning

confidence: 99%

Use of prior knowledge and extrapolation in paediatric drug development: A case study with deferasirox

Borella

Oosterholt

Magni

et al. 2019

European Journal of Pharmaceutical Sciences

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Extrapolation of enalapril efficacy from adults to children using pharmacokinetic/pharmacodynamic modelling

Abstract: Mathematical modelling was used to extrapolate enalapril efficacy to young children to support a paediatric investigation plan targeting a paediatric-use marketing authorization application.

Cited by 7 publications

References 10 publications

Simultaneous Semi-Mechanistic Population Pharmacokinetic Modeling Analysis of Enalapril and Enalaprilat Serum and Urine Concentrations From Child Appropriate Orodispersible Minitablets

Simultaneous Semi-Mechanistic Population Pharmacokinetic Modeling Analysis of Enalapril and Enalaprilat Serum and Urine Concentrations From Child Appropriate Orodispersible Minitablets

Pediatric Cardiomyopathies

Use of prior knowledge and extrapolation in paediatric drug development: A case study with deferasirox

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