Skip to main content
SpringerLink
Log in

An Integrated Paediatric Population PK/PD Analysis of dDAVP: How do PK Differences Translate to Clinical Outcomes?

  • Original Research Article
  • Published:
Clinical Pharmacokinetics Aims and scope Submit manuscript

Abstract

Introduction

The bioequivalence of two formulations of desmopressin (dDAVP), a vasopressin analogue prescribed for nocturnal enuresis treatment in children, has been previously confirmed in adults but not in children. In this study, we aimed to study the pharmacokinetics (PK) and pharmacodynamics (PD) of these two formulations, in both fasted and fed children, including patients younger than 6 years of age.

Methods

Previously published data from one PK study and one PK/PD study in children aged between 6 and 16 years were combined with a new PK/PD study in children aged between 6 months and 8 years, and analysed using population PK/PD modelling. Simulations were performed to further explore the relative bioavailability of both formulations and evaluate current dosing strategies.

Results

The complex absorption behaviour of the lyophilizate was modelled using a double input, linked to a one-compartmental model with linear elimination and an indirect response model linking dDAVP concentration to produced urine volume and osmolality. The final model described the observed data well and elucidated the complexity of bioequivalence and therapeutic equivalence of the two formulations. Simulations showed that current dosing regimens using a fixed dose of lyophilizate 120 μg is not adequate for children, assuming children to be in the fed state when taking dDAVP. A new age- and weight-based dosing regimen was suggested and was shown to lead to improved, better tailored effects.

Conclusions

Bioequivalence and therapeutic equivalence data of two formulations of the same drug in adults cannot be readily extrapolated to children. This study shows the importance of well-designed paediatric clinical trials and how they can be analysed using mixed-effects modelling to make clinically relevant inferences. A follow-up clinical trial testing the proposed dDAVP dosing regimen should be performed.

Clinical Trial Registration

This trial has been registered at www.clinicaltrials.gov (identifier NCT02584231; EudraCT 2014-005200-13).

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Kaehler ST, Steiner IM, Sauermann R, Scheidl H, Mueller M, Joukhadar C. A bioequivalence study of two oral desmopressin tablet formulations. Pharmacology. 2006;77(1):46–52.

    Article  CAS  Google Scholar 

  2. Fjellestad-Paulsen A, Wille S, Harris AS. Comparison of intranasal and oral desmopressin for nocturnal enuresis. Arch Dis Child. 1987;62(7):674–7.

    Article  CAS  Google Scholar 

  3. Rittig S, Jensen AR, Jensen KT, Pedersen EB. Effect of food intake on the pharmacokinetics and antidiuretic activity of oral desmopressin (DDAVP) in hydrated normal subjects. Clin Endocrinol (Oxf). 1998;48:235–41.

    Article  CAS  Google Scholar 

  4. Michelet R, Dossche L, de Bruyne P, Colin P, Boussery K, Vande Walle J, et al. Effects of food and pharmaceutical formulation on desmopressin pharmacokinetics in children. Clin Pharmacokinet. 2016;55(9):1159–70.

    Article  CAS  Google Scholar 

  5. Vande Walle JGJ, Bogaert GA, Mattsson S, Schurmans T, Hoebeke P, Deboe V, Norgaard JP. A new fast-melting oral formulation of desmopressin: a pharmacodynamic study in children with primary nocturnal enuresis. BJU Int. 2006;97(3):603–9.

    Article  CAS  Google Scholar 

  6. De Guchtenaere A, Van Herzeele C, Raes A, Dehoorne J, Hoebeke P, Van Laecke E, et al. Oral lyophylizate formulation of desmopressin: superior pharmacodynamics compared to tablet due to low food interaction. J Urol. 2011;185(6):2308–13.

    Article  Google Scholar 

  7. Michelet R, Dossche L, Van Herzeele C, Van Bocxlaer J, Vermeulen A, Vande Walle J. Claiming desmopressin therapeutic equivalence in children requires pediatric data: a population PKPD analysis. Eur J Clin Pharmacol. 2018;74(3):297–305.

    Article  CAS  Google Scholar 

  8. Østerberg O, Savic RM, Karlsson MO, Simonsson USH, Nørgaard JP, Vande Walle J, et al. Pharmacokinetics of desmopressin administrated as an oral lyophilisate dosage form in children with primary nocturnal enuresis and healthy adults. J Clin Pharmacol. 2006;46(10):1204–11.

    Article  Google Scholar 

  9. Gasthuys E, Vermeulen A, Croubels S, Millecam J, Schauvliege S, van Bergen T, et al. Population pharmacokinetic modeling of a desmopressin oral lyophilisate in growing piglets as a model for the pediatric population. Front Pharmacol. 2018;9:41.

    Article  Google Scholar 

  10. Dossche L, Michelet R, De Bruyne P, Gasthuys E, Rittig S, Vermeulen A, et al. What young children teach us about pharmacokinetics and pharmacodynamics of desmopressin oral lyophylisate—one size does not fit all. 2019 (manuscript under preparation).

  11. De Bruyne P, De Guchtenaere A, Van Herzeele C, Raes A, Dehoorne J, Hoebeke P, et al. Pharmacokinetics of desmopressin administered as tablet and oral lyophilisate formulation in children with monosymptomatic nocturnal enuresis. Eur J Pediatr. 2014;173(2):223–8.

    Article  Google Scholar 

  12. Anderson BJ, Holford NH. Mechanism-based concepts of size and maturity in pharmacokinetics. Annu Rev Pharmacol Toxicol. 2008;48(1):303–32.

    Article  CAS  Google Scholar 

  13. Anderson BJ, Holford NH. Mechanistic basis of using body size and maturation to predict clearance in humans. Drug Metab Pharmacokinet. 2009;24(1):25–36.

    Article  CAS  Google Scholar 

  14. Hutmacher MM, Kowalski KG. Covariate selection in pharmacometric analyses: a review of methods. Br J Clin Pharmacol. 2015;79(1):132–47.

    Article  Google Scholar 

  15. Nguyen THT, Mouksassi MS, Holford N, Al-Huniti N, Freedman I, Hooker AC. Model evaluation of continuous data pharmacometric models: metrics and graphics. CPT Pharmacomet Syst Pharmacol. 2017;6(2):87–109.

    Article  CAS  Google Scholar 

  16. Efron B. Better bootstrap confidence intervals. J Am Stat Assoc. 1987;82(397):171–85.

    Article  Google Scholar 

  17. Ferring Pharmaceuticals. MINIRIN® Melt Desmopressin Product Information File. 2007. Available online from http://secure.healthlinks.net.au/content/ferring/pi.cfm?product=fppminiw10611. Accessed 19 July 2019.

  18. Medicines and Healthcare products Requlatory Agency (MHRA). DDAVP MELT Oral Lyophilisate (Desmopressin Acetate) License File. 2006. Available online from http://www.mhra.gov.uk/home/groups/par/documents/websiteresources/con2023731.pdf. Accessed 19 July 2019.

  19. Rittig S, Kamperis K, Siggaard C, Hagstroem S, Djurhuus JC. Age related nocturnal urine volume and maximum voided volume in healthy children: reappraisal of International Children’s Continence Society definitions. J Urol. 2010;183(4):1561–7.

    Article  CAS  Google Scholar 

  20. Dossche L, Raes A, Hoebeke P, De Bruyne P, Vande Walle J. Circadian rhythm of glomerular filtration and solute handling related to nocturnal enuresis. J Urol. 2016;195(1):162–7.

    Article  CAS  Google Scholar 

  21. Hazinski MF. Understanding fluid balance in the seriously ill child. Pediatr Nurs. 1988;14(3):231–6.

    CAS  PubMed  Google Scholar 

  22. Bauer R. NONMEM users guide: introduction to NONMEM 7. Ellicott City: ICON Development Solutions; 2010. p. 1–61.

    Google Scholar 

  23. Lindbom L, Pihlgren P, Jonsson N. PsN-Toolkit—a collection of computer intensive statistical methods for non-linear mixed effect modeling using NONMEM. Comput Methods Programs Biomed. 2005;79(3):241–57.

    Article  Google Scholar 

  24. Keizer RJ, Karlsson MO, Hooker A. Modeling and simulation workbench for NONMEM: Tutorial on Pirana, PsN, and Xpose. CPT Pharmacometrics Syst Pharmacol. 2013;2:e50.

    Article  CAS  Google Scholar 

  25. Callreus T, Odeberg J, Lundin S. Indirect-response modeling of desmopressin at different levels of hydration. J Pharmacokinet Biopharm. 2000;27(5):513–29.

    Article  Google Scholar 

  26. Liu J, Sharma N, Zheng W, Ji H, Tam H, Wu X, et al. Sex differences in vasopressin V2 receptor expression and vasopressin-induced antidiuresis. Am J Physiol Renal Physiol. 2011;300(2):F433–40.

    Article  CAS  Google Scholar 

  27. Juul KV, Van Herzeele C, De Bruyne P, Goble S, Vande Walle J, Nørgaard JP. Desmopressin melt improves response and compliance compared with tablet in treatment of primary monosymptomatic nocturnal enuresis. Eur J Pediatr. 2013;172(9):1235–42.

    Article  CAS  Google Scholar 

  28. Schulman S, Stokes A, Salzman P. The efficacy and safety of oral desmopressin in children with primary nocturnal enuresis. J Urol. 2001;166(6):2427–31.

    Article  CAS  Google Scholar 

Download references

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, Jan Van Bocxlaer & An Vermeulen

  2. Department of Clinical Pharmacy and Biochemistry, Institute of Pharmacy, Freie Universitaet Berlin, Berlin, Germany

    Robin Michelet

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

    Lien Dossche, Charlotte Van Herzeele, Pauline De Bruyne, Elke Gasthuys & Johan Vande Walle

  4. Department of Clinical Psychology, General Hospital Sint-Jan Bruges-Ostend, Brugge, Belgium

    Charlotte Van Herzeele

  5. Department of Internal Medicine and Paediatrics, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium

    Lien Dossche, Pauline De Bruyne & Johan Vande Walle

  6. Department of Pharmacology, Toxicology and Biochemistry, Faculty of Veterinary Medicine, Ghent University, Ghent, Belgium

    Elke Gasthuys

Authors
  1. Robin Michelet
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lien Dossche
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Charlotte Van Herzeele
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Pauline De Bruyne
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Elke Gasthuys
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jan Van Bocxlaer
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Johan Vande Walle
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. An Vermeulen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to An Vermeulen.

Ethics declarations

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 the company. Pauline De Bruyn, Lien Dossche and Charlotte Van Herzeele received 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, as well as payment for lectures from Ferring Pharmaceuticals and Astellas Pharma. Robin Michelet, Elke Gasthuys and Jan Van Bocxlaer have no potential conflicts of interest that might be relevant to this article.

Additional information

Robin Michelet, Lien Dossche, Charlotte Van Herzeele, Pauline De Bruyne, Elke Gasthuys, Jan Van Bocxlaer, Johan Vande Walle, An Vermeulen: In name of the SAFEPEDRUG consortium, http://safepedrug.eu.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Michelet, R., Dossche, L., Van Herzeele, C. et al. An Integrated Paediatric Population PK/PD Analysis of dDAVP: How do PK Differences Translate to Clinical Outcomes?. Clin Pharmacokinet 59, 81–96 (2020). https://doi.org/10.1007/s40262-019-00798-6

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40262-019-00798-6

Search

Navigation