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

Robin Michelet (UGent) , Lien Dossche (UGent) , Charlotte Van Herzeele (UGent) , Jan Van Bocxlaer (UGent) , An Vermeulen (UGent) and Johan Vande Walle (UGent)
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Abstract
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. 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. 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-mu g lyophilisate has a more pronounced effect on the urine volume and osmolality than the 200-mu g tablet, even when the same exposure is achieved. 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.
Keywords
Bioequivalence, 1-Deamino-8-D-arginine vasopressin (dDAVP), Children, Tablet, Lyophilisate, PKPD modeling, PRIMARY NOCTURNAL ENURESIS, ORAL DESMOPRESSIN, TABLET FORMULATIONS, PHARMACOKINETICS, MODELS, VASOPRESSIN, VOLUNTEERS, ADULTS, FOOD

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Chicago
Michelet, Robin, Lien Dossche, Charlotte Van Herzeele, Jan Van Bocxlaer, An Vermeulen, and Johan Vande Walle. 2018. “Claiming Desmopressin Therapeutic Equivalence in Children Requires Pediatric Data : a Population PKPD Analysis.” European Journal of Clinical Pharmacology 74 (3): 297–305.
APA
Michelet, R., Dossche, L., Van Herzeele, C., Van Bocxlaer, J., Vermeulen, A., & Vande Walle, J. (2018). Claiming desmopressin therapeutic equivalence in children requires pediatric data : a population PKPD analysis. EUROPEAN JOURNAL OF CLINICAL PHARMACOLOGY, 74(3), 297–305.
Vancouver
1.
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. EUROPEAN JOURNAL OF CLINICAL PHARMACOLOGY. 2018;74(3):297–305.
MLA
Michelet, Robin, Lien Dossche, Charlotte Van Herzeele, et al. “Claiming Desmopressin Therapeutic Equivalence in Children Requires Pediatric Data : a Population PKPD Analysis.” EUROPEAN JOURNAL OF CLINICAL PHARMACOLOGY 74.3 (2018): 297–305. Print.
@article{8543872,
  abstract     = {For a new formulation of a drug, only pharmacokinetic bioequivalence with the original formulation has to be demonstrated in healthy, young adults. However, {\textacutedbl}children are not small adults,{\textacutedbl} 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. 
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. 
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-mu g lyophilisate has a more pronounced effect on the urine volume and osmolality than the 200-mu g tablet, even when the same exposure is achieved. 
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.},
  author       = {Michelet, Robin and Dossche, Lien and Van Herzeele, Charlotte and Van Bocxlaer, Jan and Vermeulen, An and Vande Walle, Johan},
  issn         = {0031-6970},
  journal      = {EUROPEAN JOURNAL OF CLINICAL PHARMACOLOGY},
  language     = {eng},
  number       = {3},
  pages        = {297--305},
  title        = {Claiming desmopressin therapeutic equivalence in children requires pediatric data : a population PKPD analysis},
  url          = {http://dx.doi.org/10.1007/s00228-017-2386-0},
  volume       = {74},
  year         = {2018},
}

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