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An Integrated Paediatric Population PK/PD Analysis of dDAVP: How do PK Differences Translate to Clinical Outcomes?
Robin Michelet1,2, Lien Dossche3,4, Charlotte Van Herzeele3,5
1Laboratory of Medical Biochemistry and Clinical Analysis, Department of Bioanalysis, Faculty of Pharmaceutical Sciences, Ghent University, Ghent, Belgium.
Insights
Bioequivalence of desmopressin (dDAVP) formulations in children requires specific study, as adult data is not applicable. New dosing regimens are proposed for improved therapeutic effects in pediatric patients.
Area of Science:
- Pharmacology and Therapeutics
- Pediatric Clinical Trials
Background:
- Adult bioequivalence of desmopressin (dDAVP) is established, but not in children.
- Desmopressin is a vasopressin analogue used for treating nocturnal enuresis in children.
Purpose of the Study:
- To investigate the pharmacokinetics (PK) and pharmacodynamics (PD) of two desmopressin formulations in children.
- To evaluate the bioequivalence and therapeutic equivalence of these formulations in pediatric populations, including those younger than 6 years.
- To assess the impact of fed versus fasted states on drug absorption and efficacy.
Main Methods:
- Combined data from previous and new PK/PD studies in children aged 6 months to 16 years.
- Utilized population PK/PD modeling and simulations to analyze relative bioavailability and dosing strategies.
- Employed a one-compartmental model with indirect response modeling to capture complex absorption and PD relationships.
Main Results:
- The absorption of the lyophilizate formulation was complex and accurately modeled.
- Current fixed-dose regimens (120 μg lyophilizate) are inadequate for children, especially in the fed state.
- A novel age- and weight-based dosing regimen was proposed, demonstrating potential for improved and tailored therapeutic effects.
Conclusions:
- Adult bioequivalence data for desmopressin cannot be extrapolated to children.
- Paediatric clinical trials analyzed with mixed-effects modeling are crucial for relevant inferences.
- Further clinical trials are recommended to validate the proposed desmopressin dosing regimen in children.
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).
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