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An integrated paediatric population PK/PD analysis of dDAVP : how do PK differences translate to clinical outcomes?

Robin Michelet (UGent) , Lien Dossche (UGent) , Charlotte Van Herzeele (UGent) , Pauline De Bruyne (UGent) , Elke Gasthuys (UGent) , Jan Van Bocxlaer (UGent) , Johan Vande Walle (UGent) and An Vermeulen (UGent)
(2020) CLINICAL PHARMACOKINETICS. 59(1). p.81-96
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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 mu g 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.
Keywords
Frederik Paulsen Chair, ORAL DESMOPRESSIN, PHARMACOKINETICS, CHILDREN, FORMULATION, TABLET, SIZE, FOOD

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MLA
Michelet, Robin, et al. “An Integrated Paediatric Population PK/PD Analysis of DDAVP : How Do PK Differences Translate to Clinical Outcomes?” CLINICAL PHARMACOKINETICS, vol. 59, no. 1, 2020, pp. 81–96.
APA
Michelet, R., Dossche, L., Van Herzeele, C., De Bruyne, P., Gasthuys, E., Van Bocxlaer, J., … Vermeulen, A. (2020). An integrated paediatric population PK/PD analysis of dDAVP : how do PK differences translate to clinical outcomes? CLINICAL PHARMACOKINETICS, 59(1), 81–96.
Chicago author-date
Michelet, Robin, Lien Dossche, Charlotte Van Herzeele, Pauline De Bruyne, Elke Gasthuys, Jan Van Bocxlaer, Johan Vande Walle, and An Vermeulen. 2020. “An Integrated Paediatric Population PK/PD Analysis of DDAVP : How Do PK Differences Translate to Clinical Outcomes?” CLINICAL PHARMACOKINETICS 59 (1): 81–96.
Chicago author-date (all authors)
Michelet, Robin, Lien Dossche, Charlotte Van Herzeele, Pauline De Bruyne, Elke Gasthuys, Jan Van Bocxlaer, Johan Vande Walle, and An Vermeulen. 2020. “An Integrated Paediatric Population PK/PD Analysis of DDAVP : How Do PK Differences Translate to Clinical Outcomes?” CLINICAL PHARMACOKINETICS 59 (1): 81–96.
Vancouver
1.
Michelet R, Dossche L, Van Herzeele C, De Bruyne P, Gasthuys E, Van Bocxlaer J, et al. An integrated paediatric population PK/PD analysis of dDAVP : how do PK differences translate to clinical outcomes? CLINICAL PHARMACOKINETICS. 2020;59(1):81–96.
IEEE
[1]
R. Michelet et al., “An integrated paediatric population PK/PD analysis of dDAVP : how do PK differences translate to clinical outcomes?,” CLINICAL PHARMACOKINETICS, vol. 59, no. 1, pp. 81–96, 2020.
@article{8628596,
  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 mu g 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.},
  author       = {Michelet, Robin and Dossche, Lien and Van Herzeele, Charlotte and De Bruyne, Pauline and Gasthuys, Elke and Van Bocxlaer, Jan and Vande Walle, Johan and Vermeulen, An},
  issn         = {0312-5963},
  journal      = {CLINICAL PHARMACOKINETICS},
  keywords     = {Frederik Paulsen Chair,ORAL DESMOPRESSIN,PHARMACOKINETICS,CHILDREN,FORMULATION,TABLET,SIZE,FOOD},
  language     = {eng},
  number       = {1},
  pages        = {81--96},
  title        = {An integrated paediatric population PK/PD analysis of dDAVP : how do PK differences translate to clinical outcomes?},
  url          = {http://dx.doi.org/10.1007/s40262-019-00798-6},
  volume       = {59},
  year         = {2020},
}

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