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      Model-dependent pharmacokinetic analysis of enalapril administered to healthy adult volunteers using orodispersible minitablets for use in pediatrics

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          Abstract

          Introduction

          Comparative pharmacokinetic (PK) data analysis of drugs administered using developed child-appropriate and market authorized dosage formulation is sparse and is important in pediatric drug development.

          Objectives

          To compare and evaluate any differences in PK of enalapril administered using two treatments of child-appropriate orodispersible minitablets (ODMTs) and market authorized reference tablet formulation (Renitec ®) using PK compartment model and validated least square minimization method (LSMM) of parameter estimation.

          Methods

          Full profile data sets were obtained from a phase I clinical trial, whereby three treatments of enalapril, ie, reference tablets with 240 mL water (treatment A), child-appropriate ODMTs with 240 mL (treatment B), and ODMTs dispersed in the mouth with 20 mL water (treatment C), were administered to 24 healthy adult volunteers. Virtual validation analysis was conducted using R program to select accurate and precise LSMM of parameter estimation. For the selection of PK model and estimation of parameters, enalapril data were fitted with one-and two-compartment models with first order of absorption and elimination, with and without incorporated lag time parameter (tlag). The log-transformed PK parameters were statistically compared by the two-sided paired t-test with the level of significance of P<0.05.

          Results

          One-compartment model with first-order absorption and elimination and incorporated lag time adequately predicted concentrations of enalapril. Reciprocal of predicted concentration using iteratively reweighted LSMM was selected as the most appropriate method of parameter estimation. Comparison of PK parameters including rate constant of absorption and elimination, volume of distribution, and tlag between the three treatments showed significant difference ( P=0.018) in tlag between treatments B and A only.

          Conclusion

          Compared with reference formulation, enalapril administered from child-appropriate ODMTs administered with 240 mL water appeared 4 minutes earlier in serum. No other differences were observed in absorption, elimination, and relative bioavailability of drug between the three treatment arms.

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          Most cited references 18

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          Guidance for industry, Bioanalytical method validation

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            Weighted least squares fitting using ordinary least squares algorithms

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              Heart failure in children: part I: history, etiology, and pathophysiology.

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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                1177-8881
                2019
                25 January 2019
                : 13
                : 481-490
                Affiliations
                Institute of Clinical Pharmacy and Pharmacotherapy, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany, muhammad.faisal@ 123456hhu.de
                Author notes
                Correspondence: Muhammad Faisal, Institute of Clinical Pharmacy and Pharmacotherapy, Heinrich-Heine-University Düsseldorf, Building:26.22, Room:02.21, Universitätsstrasse 1, 40225 Düsseldorf, Germany, Tel +49 021 1811 3840, Email muhammad.faisal@ 123456hhu.de
                [*]

                These authors contributed equally to this work

                Article
                dddt-13-481
                10.2147/DDDT.S188417
                6354687
                © 2019 Faisal et al. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

                Categories
                Original Research

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