Model-dependent pharmacokinetic analysis of enalapril following the administration of novel child-appropriate orodispersible mini-tablets

Despite the legislative initiatives by the regulatory European medical agency (EMA) and the United States Food and Drug Administration Authority (FDA), an approved drug with child-appropriate dosage formulations are still absent for many drugs for pediatric heart failure. The pediatric patients are usually treated by extrapolating adult treatments to children without considering the important physiological, biochemical and pathological differences. The lack of approved child-appropriate dosage formulation leads to inaccurate off-labeled extemporaneous administration of drugs. Off-labeled use of drug and dosage form has put the pediatric population at severe risk of adverse drug reactions or no therapeutic action and warrant the need to develop a safe and effective child-appropriate dosage formulation for the treatment of pediatric heart failure.

The child-appropriate orodispersible mini-tablet formulation of enalapril was developed and tested during the LENA (labeling of enalapril from neonates till adolescents) clinical trials initiated and funded by the European Union project under the 7th framework program. A 3-period 3-treatment crossover phase I clinical trial was conducted in the project in which the developed novel child-appropriate orodispersible mini-tablets and reference formulation were administered to 24 healthy adult volunteers. Full profile serum samples were analyzed using an individual pharmacokinetic modeling analysis and least square minimization method of parameter estimation to account any difference in the pharmacokinetics of enalapril when was administered from the dispersed and administered orodispersible mini-tablets and reference formulation. For the comparison of the biotransformation and pharmacokinetics of active enalaprilat from the two formulations, a combined serum and urine enalapril and enalaprilat models were developed and the maximum likelihood method of parameter estimation was used for parameter estimation. The estimated individual pharmacokinetic parameters were compared to account for any difference in the pharmacokinetics of the two formulations.

In addition, the covariate effect of the formulation was evaluated on the model parameters. The pharmacokinetic modeling analysis revealed 5 minutes of an early appearance of enalapril from the developed child-appropriate orodispersible mini-tablets administered with 240ml water compared to the reference formulation. No other difference in the pharmacokinetics of enalapril and enalaprilat was observed from the two formulations. The modeling analysis also showed that enalapril had similar bioavailability and pharmacokinetics from the orodispersible mini-tablets and the reference formulations and thus is highly suitable to be safely and effectively use in children.

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Article Information: Dissertation for Ph.D. at Heinrich-Heine-University in Dusseldorf from Muhammad Faisal, 2020.