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Simultaneous Semi-Mechanistic Population Pharmacokinetic Modeling Analysis of Enalapril and Enalaprilat Serum and Urine Concentrations From Child Appropriate Orodispersible Minitablets
- Source :
- Frontiers in Pediatrics, Vol 7 (2019), Frontiers in Pediatrics
- Publication Year :
- 2019
- Publisher :
- FRONTIERS MEDIA SA, 2019.
-
Abstract
- 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. ispartof: FRONTIERS IN PEDIATRICS vol:7 ispartof: location:Switzerland status: published
- Subjects :
- Enalaprilat
enalaprilat
Population
heart failure
TRANSIT
030204 cardiovascular system & hematology
Pharmacology
030226 pharmacology & pharmacy
Pediatrics
enalapril
child appropriate dosage forms
03 medical and health sciences
0302 clinical medicine
Pharmacokinetics
medicine
ABSORPTION
Enalapril
orodispersible mini-tablets
DRUG
education
FORMULATION
Active metabolite
NONMEM
Original Research
Volume of distribution
education.field_of_study
DISPOSITION
Science & Technology
population pharmacokinetics modeling analysis
business.industry
lcsh:RJ1-570
lcsh:Pediatrics
3. Good health
ETIOLOGY
CONVERTING ENZYME-INHIBITORS
Pharmacodynamics
Pediatrics, Perinatology and Child Health
HEART-FAILURE
business
Life Sciences & Biomedicine
medicine.drug
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- Frontiers in Pediatrics, Vol 7 (2019), Frontiers in Pediatrics
- Accession number :
- edsair.doi.dedup.....ca216c761278ef00d5c98d71bb9e7eaa