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.
Highlights
Despite the major success of the US Food and Drug Authority (FDA) and the European Medicine Agency (EMA) legislative and incentive initiatives toward pediatric drug development, the treatment of congestive heart failure in pediatrics (CHF) still lacks an approved drug and dosage formulation [1, 2]
Eta shrinkage values for most of the parameters were lower than 20 percent and the individual model predicted concentration vs. the observed serum and urine concentration plots of enalapril and enalaprilat given in Figure 2 were informative and showed agreement between the observed and predicted concentrations [35]
The semi mechanistic population pharmacokinetic model predicted the detailed pharmacokinetics of enalapril and enalaprilat in serum and urine
Summary
Despite the major success of the US Food and Drug Authority (FDA) and the European Medicine Agency (EMA) legislative and incentive initiatives toward pediatric drug development, the treatment of congestive heart failure in pediatrics (CHF) still lacks an approved drug and dosage formulation [1, 2]. Lack of approved dosage forms leads to manipulation, modification, and extemporaneous administration of drugs [3, 4]. These suboptimal practices can result in compromised safety and efficacy and emphasize the need to develop a child appropriate dosage formulations [5, 6]. Enalapril and enalaprilat are eliminated through the renal route without further metabolism. Around 60% of the administered dose is recovered in urine as enalapril and enalaprilat [11]. No other route of elimination has been reported for the enalapril and enalaprilat
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