A Pharmacokinetic and Pharmacodynamic Study of Oral Dexmedetomidine

Shubham Chamadia, Ph.D.; Juan C. Pedemonte, M.D.; Lauren E. Hobbs, M.A.; Hao Deng, M.D., M.P.H.; Sarah Nguyen, B.S.; Luis I. Cortinez, M.D.; Oluwaseun Akeju, M.D., M.M.Sc.


Anesthesiology. 2020;133(6):1223-1233. 

In This Article

Abstract and Introduction


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.


Dexmedetomidine is an alpha-2 adrenergic agonist sedative that promotes sleep neurophysiology.[1–10] It is widely administered to patients in intensive care units as a pharmacologic aid to reduce the incidence and duration of delirium.[11–15] Dexmedetomidine is only approved for use in humans as an intravenous medication. An oral formulation of dexmedetomidine is expected to broaden its sedation and delirium-sparing benefits to numerous care settings (e.g., general medical and surgical units). We recently reported that a single nighttime loading dose of intravenous dexmedetomidine promoted non–rapid eye movement stage 3 sleep, preserved regular sleep cycling, and may confer the cognitive benefits of sleep to healthy subjects.[6] This result suggests that continuous infusions of dexmedetomidine may not be necessary for sleep promotion and that dexmedetomidine could be developed as an oral sleep-enhancing medication.

Whether a solid oral formulation of dexmedetomidine will reach plasma concentrations, and by proxy, brain concentrations necessary to promote sleep neurophysiology, is unclear. In humans, plasma concentrations of dexmedetomidine between 0.2 ng/mg and 0.3 ng/ml result in rousable sedation,[16] whereas plasma concentrations above 1.9 ng/ml may be necessary for unarousable sedation.[17] Also, intravenous dexmedetomidine has been associated with a biphasic mean arterial blood pressure (MAP) response.[16–18] Low dexmedetomidine plasma concentrations (less than ~1.9 ng/ml) are associated with decreased MAP and heart rate (HR),[17] whereas high plasma concentrations (greater than ~1.9 ng/ml) are associated with increased MAP.[17] These MAP and HR findings are likely mediated through drug activity on peripheral vascular endothelium and in the central nervous system, respectively.[16,19,20] However, MAP and HR changes associated with oral dexmedetomidine have not been characterized.

Therefore, we performed a phase I dose-escalation study (n = 5, 300 mcg; followed by n = 5, 500 mcg; followed by n = 5, 700 mcg) of oral dexmedetomidine. We hypothesized that oral dexmedetomidine would be associated with hemodynamic stability (see the Materials and Methods section for definition) and plasma concentrations that are consistent with rousable sedation. We constructed a pharmacokinetic–pharmacodynamic model to characterize the relationship between plasma concentrations of dexmedetomidine, MAP, and HR data.