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Effects of Food and Pharmaceutical Formulation on Desmopressin Pharmacokinetics in Children

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Abstract

Introduction

Desmopressin is used for treatment of nocturnal enuresis in children. In this study, we investigated the pharmacokinetics of two formulations—a tablet and a lyophilisate—in both fasted and fed children.

Methods

Previously published data from two studies (one in 22 children aged 6–16 years, and the other in 25 children aged 6–13 years) were analyzed using population pharmacokinetic modeling. A one-compartment model with first-order absorption was fitted to the data. Covariates were selected using a forward selection procedure. The final model was evaluated, and sensitivity analysis was performed to improve future sampling designs. Simulations were subsequently performed to further explore the relative bioavailability of both formulations and the food effect.

Results

The final model described the plasma desmopressin concentrations adequately. The formulation and the fed state were included as covariates on the relative bioavailability. The lyophilisate was, on average, 32.1 % more available than the tablet, and fasted children exhibited an average increase in the relative bioavailability of 101 % in comparison with fed children. Body weight was included as a covariate on distribution volume, using a power function with an exponent of 0.402. Simulations suggested that both the formulation and the food effect were clinically relevant.

Conclusion

Bioequivalence data on two formulations of the same drug in adults cannot be readily extrapolated to children. This was the first study in children suggesting that the two desmopressin formulations are not bioequivalent in children at the currently approved dose levels. Furthermore, the effect of food intake was found to be clinically relevant. Sampling times for a future study were suggested. This sampling design should result in more informative data and consequently generate a more robust model.

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Author information

Authors and Affiliations

  1. Laboratory of Medical Biochemistry and Clinical Analysis, Department of Bioanalysis, Faculty of Pharmaceutical Sciences, Ghent University, Ghent, Belgium

    Robin Michelet, Pieter Colin, Koen Boussery, Jan Van Bocxlaer & An Vermeulen

  2. Department of Pediatrics and Medical Genetics, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium

    Lien Dossche & Pauline De Bruyne

  3. Department of Pediatric Nephrology, Ghent University Hospital, Ghent, Belgium

    Johan Vande Walle

  4. Department of Anesthesiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

    Pieter Colin

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  1. Robin Michelet
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  2. Lien Dossche
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  3. Pauline De Bruyne
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Corresponding author

Correspondence to Robin Michelet.

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Funding

This study was supported by the Agency for Innovation by Science and Technology in Flanders (IWT) through the SAFE-PEDRUG Project (IWT/SBO 130033).

Conflict of interest

An Vermeulen is an employee of Johnson & Johnson and holds stock/stock options in Johnson & Johnson. Pauline De Bruyne has received a travel reimbursement from Ferring Pharmaceuticals for a presentation at the Ghent-Aarhus Springschool. Johan Vande Walle has received consulting fees and travel reimbursements from Ferring Pharmaceuticals, and has received payment for lectures from Ferring Pharmaceuticals and Astellas Pharma. Robin Michelet, Lien Dossche, Pieter Colin, Koen Boussery, and Jan Van Bocxlaer have no potential conflicts of interest that might be relevant to the content of this manuscript.

Additional information

R. Michelet, L. Dossche, P. De Bruyne, J.V. Walle, J. Van Bocxlaer and A. Vermeulen: On behalf of the SAFE-PEDRUG Consortium; http://safepedrug.eu.

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Michelet, R., Dossche, L., De Bruyne, P. et al. Effects of Food and Pharmaceutical Formulation on Desmopressin Pharmacokinetics in Children. Clin Pharmacokinet 55, 1159–1170 (2016). https://doi.org/10.1007/s40262-016-0393-4

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