Paediatric population pharmacokinetic modelling to assess hydrocortisone replacement dosing regimens in young children

in European Journal of Endocrinology
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  • 1 Department of Clinical Pharmacy and Biochemistry, Institute of Pharmacy, Freie Universitaet Berlin, Berlin, Germany
  • 2 Graduate Research Training Program, PharMetrX, Berlin, Germany
  • 3 Pharmacometrics and Systems Pharmacology, University of Navarra, Pamplona, Spain
  • 4 Charité-Universitätsmedizin, Berlin, Germany
  • 5 Diurnal Limited, Cardiff, UK
  • 6 Institute of Mathematics, Universität Potsdam, Potsdam, Germany
  • 7 University of Sheffield, Sheffield, UK

Correspondence should be addressed to C Kloft; Email: charlotte.kloft@fu-berlin.de

*(R Michelet and J Melin contributed equally to this work)

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Context:

Accurate hydrocortisone dosing in children with adrenal insufficiency is important to avoid the risks of over and under treatment including iatrogenic Cushing’s syndrome and adrenal crisis.

Objective:

To establish a population pharmacokinetic model of hydrocortisone in children and use this to refine hydrocortisone replacement regimens.

Design and methods:

Pharmacokinetic study of hydrocortisone granules, available in 0.5, 1, 2 and 5 mg dose strengths, in 24 children with adrenal insufficiency aged 2 weeks to 6 years. Cortisol concentrations quantified by LC-MS/MS were used to refine an adult pharmacokinetic model to a paediatric population model which was then used to simulate seven different hydrocortisone treatment regimens.

Results:

Pre-dose cortisol levels were undetectable in 54% of the 24 children. The developed pharmacokinetic model had good predictive performance. Simulations for the seven treatment regimens using either three- or four-times daily dosing showed treatment regimens delivered an AUC0-24h within the 90% reference range for healthy children except in neonates where two regimens had an AUC below the 5th percentile. Cortisol concentrations at individual time points in the 24 h were outside the 90% reference range for healthy individuals in 50%, 55–65% and 70–75% for children, infants and neonates, respectively, with low cortisol levels being most prevalent.

Conclusions:

Current paediatric hydrocortisone treatment regimens based on either three- or four-times daily administration replicate cortisol exposure based on AUC0-24h, but the majority of cortisol levels are above or below physiological cortisol levels with low levels very common before the next dose.

Supplementary Materials

    • Supplemental Information to: “Paediatric population pharmacokinetic modelling to assess hydrocortisone replacement dosing regimens in young children”

 

     European Society of Endocrinology

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