Background

Dexmedetomidine is only approved for use in humans as an intravenous medication. An oral formulation may broaden the use and benefits of dexmedetomidine to numerous care settings. The authors hypothesized that oral dexmedetomidine (300 mcg to 700 mcg) would result in plasma concentrations consistent with sedation while maintaining hemodynamic stability.

Methods

The authors performed a single-site, open-label, phase I dose-escalation study of a solid oral dosage formulation of dexmedetomidine in healthy volunteers (n = 5, 300 mcg; followed by n = 5, 500 mcg; followed by n = 5, 700 mcg). The primary study outcome was hemodynamic stability defined as lack of hypertension, hypotension, or bradycardia. The authors assessed this outcome by analyzing raw hemodynamic data. Plasma dexmedetomidine concentrations were determined by liquid chromatograph–tandem mass spectrometry. Nonlinear mixed effect models were used for pharmacokinetic and pharmacodynamic analyses.

Results

Oral dexmedetomidine was associated with plasma concentration–dependent decreases in heart rate and mean arterial pressure. All but one subject in the 500-mcg group met our criteria for hemodynamic stability. The plasma concentration profile was adequately described by a 2-compartment, weight allometric, first-order absorption, first-order elimination pharmacokinetic model. The standardized estimated parameters for an individual of 70 kg was V1 = 35.6 [95% CI, 23.8 to 52.8] l; V2 = 54.7 [34.2 to 81.7] l; CL = 0.56 [0.49 to 0.64] l/min; and F = 7.2 [4.7 to 14.4]%. Linear models with effect sites adequately described the decreases in mean arterial pressure and heart rate associated with oral dexmedetomidine administration. However, only the 700-mcg group reached plasma concentrations that have previously been associated with sedation (>0.2 ng/ml).

Conclusions

Oral administration of dexmedetomidine in doses between 300 and 700 mcg was associated with decreases in heart rate and mean arterial pressure. Despite low oral absorption, the 700-mcg dose scheme reached clinically relevant concentrations for possible use as a sleep-enhancing medication.

Editor’s Perspective
What We Already Know about This Topic
  • Dexmedetomidine is an alpha-2 adrenergic agonist sedative that is approved for intravenous use

  • Plasma dexmedetomidine concentrations between 0.2 ng/mg and 0.3 ng/ml result in rousable sedation

  • Low plasma dexmedetomidine concentrations are associated with decreased mean arterial pressure and heart rate

What This Article Tells Us That Is New
  • The hypotheses that oral dexmedetomidine would be associated with hemodynamic stability and plasma concentrations consistent with rousable sedation were tested in a phase I dose-escalation study in 15 normal volunteers

  • Oral dexmedetomidine bioavailability was low (7.2% [95% CI, 4.7 to 14%])

  • Oral dexmedetomidine (300 µg, 500 µg, and 700 µg) was associated with plasma concentration–dependent decreases in mean arterial pressure and heart rate

  • Only the 700-µg oral dose produced plasma concentrations associated with sedation

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