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

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.

Keywords: Dexmedetomidine; Mechanism-based modeling; Norepinephrine; Pharmacodynamics; Population pharmacokinetics; α2-adrenoceptor agonist.

Conflict of interest statement

Conflicts of interest The authors declare that they have no conflicts of interest.

Figures

Fig. 1

PK/PD model diagram for the effects of dexmedetomidine on inhibition of norepinephrine (NE) release, and biophase model for NE control of blood pressure (SAP and DAP) and heart rate, subjective effects, and bispectral index

Fig. 2

Dexmedetomidine concentrations in plasma after IV (closed circles) and IN (open circles) administration to six healthy male volunteers. Solid lines represent individual predictions

Fig. 3

Norepinephrine and epinephrine concentrations in plasma after IV and IN administration of dexmedetomidine. The circles and whiskers represent the median values and interquartile ranges (closed for IV and open for IN). The lines represent population predictions (solid for IV and dashed for IN)

Fig. 4

Blood pressure and heart rate measurements versus time. Symbols and lines are as defined in Fig. 3

Fig. 5

Simulated profiles of blood pressure and heart rate vs. norepinephrine concentrations in the effect compartment using the fitted model and parameter estimates. The circles represent the median values and vertical lines are the interquartile ranges of the observed data in this study

Fig. 6

Bispectral index and subjective effects versus time. Symbols and lines are as defined in Fig. 3