Pharmacokinetics and Sedative Effects of Intranasal Dexmedetomidine in Ambulatory Pediatric Patients.

BACKGROUND: Our aim was to characterize the pharmacokinetics and sedative effects of intranasally (IN) administered dexmedetomidine used as an adjuvant in pediatric patients scheduled for magnetic resonance imaging (MRI) requiring sedation. METHODS: This was an open-label, single-period study without randomization. Pediatric patients from 5 months to 11 years of age scheduled for MRI and receiving IN dexmedetomidine for premedication as part of their care were included in this clinical trial. Single doses of 2-3 µg·kg of dexmedetomidine were applied IN approximately 1 hour before MRI. Five or 6 venous blood samples were collected over 4 hours for dexmedetomidine concentration analysis. Sedation was monitored with Comfort-B scores, and vital signs were recorded. Pharmacokinetic variables were calculated with noncompartmental methods and compared between 3 age groups (between 1 and 24 months, from 24 months to 6 years, and over 6-11 years). RESULTS: We evaluated 187 consecutive patients for suitability, of which 132 were excluded. Remaining 55 patients were recruited, of which 5 were excluded before the analysis. Data from 50 patients were analyzed. The average (standard deviation [SD]) dose-corrected peak plasma concentration (Cmax) was 0.011 liter (0.0051), and the median (interquartile range [IQR]) time to reach peak concentration (tmax) was 37 minutes (30-45 minutes). There was negative correlation with Cmax versus age (r = -0.58; 95% confidence interval [CI], -0.74 to -0.37; P < .001), but not with tmax (r = -0.14; 95% CI, 0.14-0.39; P = .35). Dose-corrected areas under the concentration-time curve were negatively correlated with age (r = -0.53; 95% CI, 0.70 to -0.29; P < .001). Median (IQR) maximal reduction in Comfort-B sedation scores was 8 (6-9), which was achieved 45 minutes (40-48 minutes) after dosing. Median (IQR) decrease in heart rate was 15% (9%-23%) from the baseline. CONCLUSIONS: Dexmedetomidine is relatively rapidly absorbed after IN administration and provides clinically meaningful but short-lasting sedation in pediatric patients.

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

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.

Bioavailability of dexmedetomidine after intranasal administration.

PURPOSE: The aim of this proof-of-concept study was to characterize the pharmacokinetics and pharmacodynamics of intranasal dexmedetomidine compared with its intravenous administration in a small number of healthy volunteers. METHODS: Single doses of 84 µg of dexmedetomidine were given once intravenously and once intranasally to seven healthy men. Plasma dexmedetomidine concentrations were measured for 10 h, and pharmacokinetic variables were calculated with standard noncompartmental methods. Heart rate, blood pressure, concentrations of adrenaline and noradrenaline in plasma, and central nervous system drug effects (with the Maddox wing, Bispectral Index, and three visual analog scales) were monitored to assess the pharmacological effects of dexmedetomidine. RESULTS: Six individuals were included in the analyses. Following intranasal administration, peak plasma concentrations of dexmedetomidine were reached in 38 (15-60) min and its absolute bioavailability was 65% (35-93%) (medians and ranges). Pharmacological effects were similar with both routes of administration, but their onset was more rapid after intravenous administration. CONCLUSIONS: Dexmedetomidine is rather rapidly and efficiently absorbed after intranasal administration. Compared with intravenous administration, intranasal administration may be a feasible alternative in patients requiring light sedation.

Dexmedetomidine pharmacokinetics in pediatric intensive care--a pooled analysis.

BACKGROUND: Published dexmedetomidine pharmacokinetic studies in children are limited by participant numbers and restricted pathology. Pooling the available studies allows investigation of covariate effects. METHODS: Data from four studies investigating dexmedetomidine pharmacokinetics after i.v. administration (n = 95) were combined to undertake a population pharmacokinetic analysis of dexmedetomidine time-concentration profiles (730 observations) using nonlinear mixed effects modeling (NONMEM). Estimates were standardized to a 70-kg adult using allometric size models. RESULTS: Children had a mean age of 3.8 (median 3 years, range 1 week-14 years) and weight of 16.0 kg (median 13.3 kg, range 3.1-58.9 kg). Population parameter estimates (between subject variability) for a two-compartment model were clearance (CL) 42.1 (CV 30.9%) lx h(-1) x 70 kg(-1), central volume of distribution (V1) 56.3 (61.3%) l.70 kg(-1), inter-compartment clearance (Q) 78.3 (37.0%) l x h(-1) x 70 kg(-1) and peripheral volume of distribution (V2) 69.0 (47.0%) l.70 kg(-1). Clearance maturation with age was described using the Hill equation. Clearance increases from 18.2 l x h(-1) x 70 kg(-1) at birth in a term neonate to reach 84.5% of the mature value by 1 year of age. Children given infusion after cardiac surgery had 27% reduced clearance compared to a population given bolus dose. Simulation of published infusion rates that provide adequate sedation for intensive care patients found a target therapeutic concentration of between 0.4 and 0.8 microg x l(-1). CONCLUSIONS: The sedation target concentration is similar to that described for adults. Immature clearance in the first year of life and a higher clearance (when expressed as l x h(-1) x kg(-1)) in small children dictate infusion rates that change with age. Extrapolation of dose from children given infusion in intensive care after cardiac surgery may not be applicable to those sedated for noninvasive procedures out of intensive care.