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Effects of food and pharmaceutical formulation on desmopressin pharmacokinetics in children

Robin Michelet (UGent) , Lien Dossche (UGent) , Pauline De Bruyne (UGent) , Pieter Colin (UGent) , Koen Boussery (UGent) , Johan Vande Walle (UGent) , Jan Van Bocxlaer (UGent) and An Vermeulen (UGent)
(2016) CLINICAL PHARMACOKINETICS. 55(9). p.1159-1170
Author
Organization
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.
Keywords
MONOSYMPTOMATIC NOCTURNAL ENURESIS, POPULATION PHARMACOKINETICS, SAFETY, TABLET, NONMEM, MODEL

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Citation

Please use this url to cite or link to this publication:

MLA
Michelet, Robin et al. “Effects of Food and Pharmaceutical Formulation on Desmopressin Pharmacokinetics in Children.” CLINICAL PHARMACOKINETICS 55.9 (2016): 1159–1170. Print.
APA
Michelet, R., Dossche, L., De Bruyne, P., Colin, P., Boussery, K., Vande Walle, J., Van Bocxlaer, J., et al. (2016). Effects of food and pharmaceutical formulation on desmopressin pharmacokinetics in children. CLINICAL PHARMACOKINETICS, 55(9), 1159–1170.
Chicago author-date
Michelet, Robin, Lien Dossche, Pauline De Bruyne, Pieter Colin, Koen Boussery, Johan Vande Walle, Jan Van Bocxlaer, and An Vermeulen. 2016. “Effects of Food and Pharmaceutical Formulation on Desmopressin Pharmacokinetics in Children.” Clinical Pharmacokinetics 55 (9): 1159–1170.
Chicago author-date (all authors)
Michelet, Robin, Lien Dossche, Pauline De Bruyne, Pieter Colin, Koen Boussery, Johan Vande Walle, Jan Van Bocxlaer, and An Vermeulen. 2016. “Effects of Food and Pharmaceutical Formulation on Desmopressin Pharmacokinetics in Children.” Clinical Pharmacokinetics 55 (9): 1159–1170.
Vancouver
1.
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. CLINICAL PHARMACOKINETICS. 2016;55(9):1159–70.
IEEE
[1]
R. Michelet et al., “Effects of food and pharmaceutical formulation on desmopressin pharmacokinetics in children,” CLINICAL PHARMACOKINETICS, vol. 55, no. 9, pp. 1159–1170, 2016.
@article{7253190,
  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.},
  author       = {Michelet, Robin and Dossche, Lien and De Bruyne, Pauline and Colin, Pieter and Boussery, Koen and Vande Walle, Johan and Van Bocxlaer, Jan and Vermeulen, An},
  issn         = {0312-5963},
  journal      = {CLINICAL PHARMACOKINETICS},
  keywords     = {MONOSYMPTOMATIC NOCTURNAL ENURESIS,POPULATION PHARMACOKINETICS,SAFETY,TABLET,NONMEM,MODEL},
  language     = {eng},
  number       = {9},
  pages        = {1159--1170},
  title        = {Effects of food and pharmaceutical formulation on desmopressin pharmacokinetics in children},
  url          = {http://dx.doi.org/10.1007/s40262-016-0393-4},
  volume       = {55},
  year         = {2016},
}

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