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Midazolam Pharmacokinetics in Obese and Non-obese Children and Adolescents

  • Christina GadeEmail author
  • Eva Sverrisdóttir
  • Kim Dalhoff
  • Jesper Sonne
  • Mia Østergaard Johansen
  • Hanne Rolighed Christensen
  • Jürgen Burhenne
  • Gerd Mikus
  • Jens Christian Holm
  • Trine Meldgaard Lund
  • Helle Holst
Original Research Article

Abstract

Background

Midazolam is a first-line drug for the treatment of status epilepticus, both by buccal and intravenous administration. In children and adolescents with obesity, midazolam pharmacokinetics may be altered, and the current dosing guidelines may therefore be insufficient.

Objective

The objective of this study was to investigate the pharmacokinetics of midazolam, after intravenous administration, in obese and non-obese adolescents aged 11–18 years.

Methods

All trial participants received a 1-µg midazolam microdose as an intravenous bolus. 13 blood samples were collected per participant at pre-specified timepoints. Plasma concentration–time data were fitted to pharmacokinetic models using non-linear mixed-effects modeling. Covariates such as weight, age, and body mass index standard deviation score were tested to explain the inter-individual variability associated with the pharmacokinetic parameters.

Results

Sixty-seven adolescents were included in the analysis. The pharmacokinetics of midazolam was best described with a two-compartment model. The rate of distribution was faster, and the peripheral volume of distribution was larger in adolescents with a high body mass index standard deviation score compared with adolescents with a lower standard deviation score. Simulations revealed that long-term infusions based on total body weight could lead to high plasma concentrations in adolescents with obesity. Furthermore, simulated plasma concentrations after a fixed buccal dose indicated that adolescents with obesity may be at risk of sub-therapeutic midazolam plasma concentrations.

Conclusions

The body mass index standard deviation score was shown to have a significant influence on the peripheral volume of distribution and the inter-compartmental clearance of midazolam. The current dosing guidelines for status epilepticus, where the midazolam dose is adjusted to total body weight or age, may lead to supra- and sub-therapeutic plasma concentrations, respectively, in adolescents with obesity.

Trial registration

EudraCT: 2014-004554-34.

Notes

Acknowledgements

The authors thank Jens Peter Kampmann for support with the study design and Søren Bøgevig for support with the clinical study and preparation of the manuscript.

Compliance with Ethical Standards

Funding

The study was funded by the Danish Regions’ “Medicinpuljen”. The funder had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Conflict of interest

Christina Gade, Mia Østergaard Johansen, Eva Sverrisdóttir, Kim Dahloff, Hanne Rolighed Christensen, Gerd Mikus, Jesper Sonne, Jürgen Burhenne, Jens Christian Holm, Trine Meldgaard Lund and Helle Holst declare that they have no potential conflicts of interest that might be relevant to this work.

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Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Christina Gade
    • 1
    Email author
  • Eva Sverrisdóttir
    • 2
  • Kim Dalhoff
    • 1
  • Jesper Sonne
    • 1
  • Mia Østergaard Johansen
    • 3
  • Hanne Rolighed Christensen
    • 1
  • Jürgen Burhenne
    • 4
  • Gerd Mikus
    • 4
  • Jens Christian Holm
    • 3
  • Trine Meldgaard Lund
    • 2
  • Helle Holst
    • 1
  1. 1.Department of Clinical PharmacologyCopenhagen University HospitalCopenhagenDenmark
  2. 2.Department of Drug Design and PharmacologyUniversity of CopenhagenCopenhagenDenmark
  3. 3.Children’s Obesity Clinic, European Center of Management (EASO), Department of PediatricsZealand University HospitalHolbaekDenmark
  4. 4.Department of Clinical Pharmacology and PharmacoepidemiologyUniversity of HeidelbergHeidelbergGermany

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