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Claiming desmopressin therapeutic equivalence in children requires pediatric data: a population PKPD analysis

  • Pharmacokinetics and Disposition
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

For a new formulation of a drug, only pharmacokinetic bioequivalence with the original formulation has to be demonstrated in healthy, young adults. However, “children are not small adults,” and to guarantee a safe and effective treatment, age-adapted drug development is required. Desmopressin, a vasopressin analogue prescribed for nocturnal enuresis in children, was studied as an example formulation first developed in adults and then extrapolated to a pediatric indication.

Methods

Population pharmacokinetic and pharmacodynamic modeling was used to analyze previously published desmopressin data of 18 children suffering from nocturnal enuresis. The main objective was the comparison of the therapeutic equivalence of two desmopressin formulations: tablet and lyophilisate. The measurements for pharmacokinetics and pharmacodynamics were respectively plasma desmopressin concentration and urine osmolality and diuresis.

Results

The half maximal inhibitory concentration for inhibition of urine production was 0.7 pg/mL lower for the lyophilisate than for the tablet. The effect of formulation on the half maximal inhibitory concentration seems to suggest that the 120-μg lyophilisate has a more pronounced effect on the urine volume and osmolality than the 200-μg tablet, even when the same exposure is achieved.

Conclusions

A new indirect response model for desmopressin was constructed and validated, using a previously built pharmacokinetic model and additional pharmacodynamic data. In order to draw solid conclusions regarding the efficacy and safety of desmopressin in children, pharmacokinetics and pharmacodynamics data should be analyzed together. This study adds proof to potential differences in pediatric and adult pharmacokinetic and pharmacodynamic properties of desmopressin and exemplifies the need for pediatric clinical trials, not only for every new drug but also for every new formulation.

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Acknowledgements

This study was funded by the “Agency for Innovation by Science and Technology in Flanders (IWT)” through the “SAFE-PEDRUG” project (IWT-SBO 130033).

Contributions of authors statement

C. Van Herzeele, A. Vermeulen, and J. Vande Walle conceptualized the study. L. Dossche and J. Vande Walle prepared and delivered the dataset. R. Michelet and L. Dossche contributed equally to the interpretation of the data for the work, literature search, drafting of the initial manuscript, and revising of the subsequent drafts. R. Michelet and A. Vermeulen performed the population PKPD modeling analysis. C. Van Herzeele, J. Van Bocxlaer, A. Vermeulen, and J. Vande Walle critically reviewed and revised the manuscript. All the authors approve the final manuscript as submitted. All the authors agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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Author notes

  1. Robin Michelet and Lien Dossche contributed equally to this work.

Authors and Affiliations

  1. Laboratory of Medical Biochemistry and Clinical Analysis, Department of Bioanalysis, Faculty of Pharmaceutical Sciences, Ghent University, Ottergemsesteenweg 460, 9000, Ghent, Belgium

    Robin Michelet, Jan Van Bocxlaer & An Vermeulen

  2. Department of Pediatric Nephrology, Ghent University Hospital, De Pintelaan 185, 9000, Ghent, Belgium

    Lien Dossche, Charlotte Van Herzeele & Johan Vande Walle

Authors
  1. Robin Michelet
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  2. Lien Dossche
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  3. Charlotte Van Herzeele
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  4. Jan Van Bocxlaer
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  5. An Vermeulen
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Consortia

On behalf of the SAFE-PEDRUG consortium

Corresponding authors

Correspondence to Robin Michelet or Lien Dossche.

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Conflicts of interest

This study was funded by the “Agency for Innovation by Science and Technology in Flanders (IWT)” through the “SAFE-PEDRUG” project (IWT-SBO 130033).

L. Dossche received a travel reimbursement from Ferring Pharmaceuticals for a presentation at the Ghent-Aarhus Spring School.

R. Michelet declares that he has no conflict of interest.

C. Van Herzeele received a travel reimbursement from Ferring Pharmaceuticals for a presentation at the Ghent-Aarhus Spring School.

A. Vermeulen is a part-time employee of Janssen R&D and holds stock/stock options of J&J.

J. Van Bocxlaer declares that he has no conflict of interest.

J. Vande Walle has received consulting fees and travel reimbursements from Ferring Pharmaceuticals and payment for lectures from Ferring pharmaceuticals and Astellas Pharma.

R. Michelet J. Van Bocxlaer declares that they have no conflict of interest.

Ethical approval

“All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.”

Informed consent

“Informed consent was obtained from all individual participants included in the study.”

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Michelet, R., Dossche, L., Van Herzeele, C. et al. Claiming desmopressin therapeutic equivalence in children requires pediatric data: a population PKPD analysis. Eur J Clin Pharmacol 74, 297–305 (2018). https://doi.org/10.1007/s00228-017-2386-0

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  • DOI: https://doi.org/10.1007/s00228-017-2386-0

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