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Subcutaneously administered dexmedetomidine is efficiently absorbed and is associated with attenuated cardiovascular effects in healthy volunteers

  • Pharmacokinetics and Disposition
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

Palliative care patients often need sedation to alleviate intractable anxiety, stress, and pain. Dexmedetomidine is used for sedation of intensive care patients, but there is no prior information on its subcutaneous (SC) administration, a route that would be favored in palliative care. We compared the pharmacokinetics and cardiovascular, sympatholytic, and sedative effects of SC and intravenously (IV) administered dexmedetomidine in healthy volunteers.

Methods

An open two-period, cross-over design with balanced randomization was used. Ten male subjects were randomized to receive 1 μg/kg dexmedetomidine both IV and SC. Concentrations of dexmedetomidine and catecholamines in plasma were measured. Pharmacokinetic variables were calculated with non-compartmental methods. In addition, cardiovascular and sedative drug effects were monitored.

Results

Eight subjects completed both treatment periods. Peak concentrations of dexmedetomidine were observed 15 min after SC administration (median; range 15–240). The mean bioavailability of SC dexmedetomidine was 81% (AUC0-∞ ratio × 100%, range 49–97%). The mean (SD) peak concentration of dexmedetomidine in plasma was 0.3 (0.1) ng/ml, and plasma concentrations associated with sedative effects (i.e., > 0.2 ng/ml) were maintained for 4 h after SC dosing. Plasma noradrenaline concentrations were significantly lower (P < 0.001) within 3 h after IV than after SC administration. Subjective scores for vigilance and performance were significantly lower 0–60 min after IV than SC dosing (P < 0.001 for both). The onset of the cardiovascular, sympatholytic, and sedative effects of dexmedetomidine was clearly less abrupt after SC than IV administration.

Conclusions

Dexmedetomidine is relatively rapidly and efficiently absorbed after SC administration. Subcutaneous dexmedetomidine may be a feasible alternative in palliative sedation, and causes attenuated cardiovascular effects compared to IV administration.

ClinicalTrials.gov identifier

NCT02724098. EUDRA CT number 2015-004698-34.

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Acknowledgements

We thank Mrs. Elina Kahra (medical laboratory technologist, Clinical Pharmacology, TYKSLAB, Hospital District of Southwest Finland, Turku, Finland) for skillful technical assistance. This study was supported financially by Turku University Hospital research fund (EVO grants 13693 and 13821), Turku, Finland.

Author information

Authors and Affiliations

  1. Department of Anaesthesiology and Intensive Care, University of Turku, P.O. Box 51, (Kiinamyllynkatu 4-8), 20521, Turku, Finland

    P. Uusalo, I. Tilli & T. I. Saari

  2. Perioperative Services, Intensive Care and Pain Medicine, Turku University Hospital, Turku, Finland

    P. Uusalo, R. A. Aantaa & T. I. Saari

  3. Institute of Biomedicine, University of Turku, and Unit of Clinical Pharmacology, Turku University Hospital, Turku, Finland

    D. Al-Ramahi & M. Scheinin

Authors
  1. P. Uusalo
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  2. D. Al-Ramahi
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  3. I. Tilli
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  4. R. A. Aantaa
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  5. M. Scheinin
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  6. T. I. Saari
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Contributions

Panu Uusalo took care of the clinical phase of the study and data collection, participated in data analysis and statistical analysis and wrote the manuscript. Darin Al-Ramahi performed the analytical assays. Ida Tilli took care of the clinical phase of the study and data collection and participated in data analysis. Riku Aantaa designed the study, wrote the protocol, supervised and coordinated the clinical implementation of the study, and participated in data analysis. Mika Scheinin supervised the analytical assays, participated in data analysis and statistical analysis and writing of the manuscript. Teijo Saari designed the study, analyzed the data, performed data and statistical analysis, and wrote the manuscript. All authors materially participated in the research and/or manuscript preparation. All authors have contributed to and approved the final manuscript.

Corresponding author

Correspondence to P. Uusalo.

Ethics declarations

The study protocol (EudraCT 2015-004698-34, ClinicalTrials.gov identifier NCT02724098) conformed to the revised Declaration of Helsinki [20] and was approved by the Ethics Committee of the Hospital District of Southwest Finland and by the Finnish National Agency for Medicines. Written informed consent was obtained from all study participants.

Conflict of interests

M. Scheinin has been engaged in contract research for Orion Pharma, the manufacturer of dexmedetomidine. T. Saari has received honoraria for speaking at symposia organized by Orion Pharma. P. Uusalo has received a speaker’s fee from Orion Pharma. D. Al-Ramahi is currently employed by Orion Pharma, but had no affiliation with the company at the time of this study. The other authors declare no conflicts of interest.

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R. Aantaa is demised

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Uusalo, P., Al-Ramahi, D., Tilli, I. et al. Subcutaneously administered dexmedetomidine is efficiently absorbed and is associated with attenuated cardiovascular effects in healthy volunteers. Eur J Clin Pharmacol 74, 1047–1054 (2018). https://doi.org/10.1007/s00228-018-2461-1

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  • DOI: https://doi.org/10.1007/s00228-018-2461-1

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