A Pharmacokinetic and Pharmacodynamic Study of Oral Dexmedetomidine

Abstract

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.

Conflict of interest statement

Conflicts of Interest: O.A. has received speaker’s honoraria from Masimo Corporation, and is listed as an inventor on a patent on brain monitoring during general anesthesia and sedation that is assigned to Massachusetts General Hospital. O.A. has received institutionally distributed royalty from this licensed patent. Funds from División de Anestesiología, Escuela de Medicina, Pontificia Universidad Católica de Chile to JP and LC. All other authors declare that no competing interests exist.

Copyright © 2020, the American Society of Anesthesiologists, Inc. All Rights Reserved.

Figures

Fig. 1.

Dexmedetomidine plasma concentration, mean arterial blood pressure, and mean heart rate. (A) Dexmedetomidine plasma concentration measured by liquid chromatograph-tandem mass spectrometry. The mean plasma concentration for the 500-mcg group was lower than the 300-mcg and 700-mcg groups at all time points beginning 30 minutes after drug administration. Vertical error bars represent the standard deviation. Dotted black line at 0.05 ng/ml represents the lower limit of sensitivity (B) Group mean arterial blood pressure. The line represents a smoothed best fit line to the data. Shaded colored bubbles represent the mean of arterial pressure over each group. (C) Group mean heart rate. The line represents a smoothed best-fit line to the data. Shaded colored bubbles represent the mean of heart rate over each group. Blue color represents the 300-mcg group (n = 5), red color represents the 500-mcg group (n = 5), and the green color represents the 700-mcg (n = 5). Mcg, micrograms.

Fig. 2.

Visual predictive check (VPC) plots. Dexmedetomidine plasma concentration of (A) our oral study group (n=10) and (B) pooled intravenous study group (n=13). Solid black line indicates 50 percentiles and dashed black lines indicate 2.5 and 97.5 percentiles of observation. Shaded area indicates 95% prediction interval. The VPC plot confirms the adequacy of model predictions, showing no apparent deviations between model and data. The 95% confidence interval and median for observed data lies within the predicted intervals obtained by simulation.

Fig. 3.

Visual predictive check (VPC) plots. (A) Mean arterial blood pressure and (B) heart rate versus time. Solid black line indicates 50 percentiles and dashed black lines indicate 2.5 and 97.5 percentiles of observation. Shaded area indicates 95% prediction interval. The VPC plot confirms the adequacy of model predictions, showing no apparent deviations between model and data. The 95% confidence interval and median for observed data lies within the predicted intervals obtained by simulation.