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Population pharmacodynamic modelling of lorazepam- and midazolam-induced sedation upon long-term continuous infusion in critically ill patients

  • Pharmacodynamics
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Abstract

Objective

The objective of the present investigation was to develop a population pharmacodynamic model for midazolam- and lorazepam-induced sedation upon long-term continuous infusion in critically ill patients.

Methods

The study was conducted in 59 patients receiving lorazepam and 54 patients receiving midazolam by continuous infusion for at least 24 h. Repeated blood samples were obtained for determination of the concentrations of lorazepam and midazolam. The level of sedation was assessed using a 5-point sedation scale.

Results

The pharmacokinetics of lorazepam and midazolam was described with previously proposed pharmacokinetic models. For the pharmacodynamics, the probability that the sedation was equal to or more than a specific score was described using a sigmoid Emax model. The EC50 values of lorazepam for the sedation scores equal or larger than 2–5 were 6.1, 57, 184 and 529 ng/ml, respectively. The corresponding values for midazolam were 216, 483, 1100 and 2200 ng/ml. Inter-individual variability in the EC50 values was relatively high with a CV of 68% for lorazepam and 86% for midazolam (p=0.035). No covariates explaining part of the observed inter-individual variability were identified.

Conclusion

The population pharmacodynamic model shows a similarly wide intra- and inter-individual variability in the pharmacodynamics of both lorazepam and midazolam. Thus, the previously observed differences in “ease of titration” between lorazepam and midazolam are unrelated to pharmacodynamic factors.

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Authors and Affiliations

  1. Department of Pharmacy, Vrije Universiteit Medical Center, Amsterdam, The Netherlands

    Eleonora L. Swart

  2. Clinical Pharmacology-Modeling & Simulation Group, F. Hoffmann-La Roche Ltd, Basel, Switzerland

    Klaas P. Zuideveld

  3. Division of Pharmacology, Leiden/Amsterdam Center for Drug Research, Leiden University, Leiden, The Netherlands

    Joost de Jongh & Meindert Danhof

  4. Department of Intensive Care, Vrije Universiteit Medical Center, Amsterdam, The Netherlands

    Lambertus G. Thijs & Robert M. J. Strack van Schijndel

Authors
  1. Eleonora L. Swart
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  2. Klaas P. Zuideveld
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  3. Joost de Jongh
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  4. Meindert Danhof
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  5. Lambertus G. Thijs
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  6. Robert M. J. Strack van Schijndel
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Corresponding author

Correspondence to Eleonora L. Swart.

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Swart, E.L., Zuideveld, K.P., de Jongh, J. et al. Population pharmacodynamic modelling of lorazepam- and midazolam-induced sedation upon long-term continuous infusion in critically ill patients. Eur J Clin Pharmacol 62, 185–194 (2006). https://doi.org/10.1007/s00228-005-0085-8

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  • DOI: https://doi.org/10.1007/s00228-005-0085-8

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