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Mechanism-based population pharmacokinetic and pharmacodynamic modeling of intravenous and intranasal dexmedetomidine in healthy subjects

  • Pharmacodynamics
  • Published:
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Abstract

Purpose

Dexmedetomidine is an α2-adrenoceptor agonist used for perioperative and intensive care sedation. This study develops mechanism-based population pharmacokinetic-pharmacodynamic models for the cardiovascular and central nervous system (CNS) effects of intravenously (IV) and intranasally (IN) administered dexmedetomidine in healthy subjects.

Method

Single doses of 84 μg of dexmedetomidine were given once IV and once IN to six healthy men. Plasma dexmedetomidine concentrations were measured for 10 h along with plasma concentrations of norepinephrine (NE) and epinephrine (E). Blood pressure, heart rate, and CNS drug effects (three visual analog scales and bispectral index) were monitored to assess the pharmacological effects of dexmedetomidine. PK-PD modeling was performed for recently published data (Eur J Clin Pharmacol 67: 825, 2011).

Results

Pharmacokinetic profiles for both IV and IN doses of dexmedetomidine were well fitted using a two-compartment PK model. Intranasal bioavailability was 82 %. Dexmedetomidine inhibited the release of NE and E to induce their decline in blood. This decrease in NE was captured with an indirect response model. The concentrations of the mediator NE served via a biophase/transduction step and nonlinear pharmacologic functions to produce reductions in blood pressure and heart rate, while a direct effect model was used for the CNS effects.

Conclusion

The comprehensive panel of two biomarkers and seven response measures were well captured by the population PK/PD models. The subjects were more sensitive to the CNS (lower EC 50 values) than cardiovascular effects of dexmedetomidine.

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Acknowledgments

Supported by NIH Grants 57980 and 24211.

Conflicts of interest

The authors declare that they have no conflicts of interest.

Authors’ contributions

HY and WJJ performed PK/PD modeling and contributed to writing of the manuscript. TI, SV, TM, RA, MH, MS, and KTO performed the original clinical studies [17] and contributed to writing the manuscript.

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Authors and Affiliations

  1. Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, 404 Kapoor Hall, State University of New York at Buffalo, Buffalo, NY, 14214, USA

    Heedoo Yoo & William J. Jusko

  2. Department of Anaesthesiology, Intensive Care, Emergency Care and Pain Medicine, University of Turku and Turku University Hospital, FI-20521, Turku, Finland

    Timo Iirola, Sanna Vilo, Tuula Manner & Riku Aantaa

  3. Department of Pharmacology, Drug Development and Therapeutics, University of Turku and Unit of Clinical Pharmacology, TYKSLAB, FI-20520, Turku, Finland

    Maria Lahtinen & Mika Scheinin

  4. Department of Anaesthesiology, Intensive Care and Pain Medicine, University of Helsinki and Helsinki University Hospital, Haartmaninkatu 4, PO Box 340, FI-00029 HUS, Helsinki, Finland

    Klaus T. Olkkola

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  1. Heedoo Yoo
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  2. Timo Iirola
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Correspondence to William J. Jusko.

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Yoo, H., Iirola, T., Vilo, S. et al. Mechanism-based population pharmacokinetic and pharmacodynamic modeling of intravenous and intranasal dexmedetomidine in healthy subjects. Eur J Clin Pharmacol 71, 1197–1207 (2015). https://doi.org/10.1007/s00228-015-1913-0

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  • DOI: https://doi.org/10.1007/s00228-015-1913-0

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