Pharmacokinetics of prolonged infusion of high-dose dexmedetomidine in critically ill patients

Abstract

Introduction: Only limited information exists on the pharmacokinetics of prolonged (> 24 hours) and high-dose dexmedetomidine infusions in critically ill patients. The aim of this study was to characterize the pharmacokinetics of long dexmedetomidine infusions and to assess the dose linearity of high doses. Additionally, we wanted to quantify for the first time in humans the concentrations of H-3, a practically inactive metabolite of dexmedetomidine.

Methods: Thirteen intensive care patients with mean age of 57 years and Simplified Acute Physiology Score (SAPS) II score of 45 were included in the study. Dexmedetomidine infusion was commenced by using a constant infusion rate for the first 12 hours. After the first 12 hours, the infusion rate of dexmedetomidine was titrated between 0.1 and 2.5 μg/kg/h by using predefined dose levels to maintain sedation in the range of 0 to -3 on the Richmond Agitation-Sedation Scale. Dexmedetomidine was continued as long as required to a maximum of 14 days. Plasma dexmedetomidine and H-3 metabolite concentrations were measured, and pharmacokinetic variables were calculated with standard noncompartmental methods. Safety and tolerability were assessed by adverse events, cardiovascular signs, and laboratory tests.

Results: The following geometric mean values (coefficient of variation) were calculated: length of infusion, 92 hours (117%); dexmedetomidine clearance, 39.7 L/h (41%); elimination half-life, 3.7 hours (38%); and volume of distribution during the elimination phase, 223 L (35%). Altogether, 116 steady-state concentrations were found in 12 subjects. The geometric mean value for clearance at steady state was 53.1 L/h (55%). A statistically significant linear relation (r2 = 0.95; P < 0.001) was found between the areas under the dexmedetomidine plasma concentration-time curves and cumulative doses of dexmedetomidine. The elimination half-life of H-3 was 9.1 hours (37%). The ratio of AUC0-∞ of H-3 metabolite to that of dexmedetomidine was 1.47 (105%), ranging from 0.29 to 4.4. The ratio was not statistically significantly related to the total dose of dexmedetomidine or the duration of the infusion.

Conclusions: The results suggest linear pharmacokinetics of dexmedetomidine up to the dose of 2.5 μg/kg/h. Despite the high dose and prolonged infusions, safety findings were as expected for dexmedetomidine and the patient population.

Trial registration: ClinicalTrials.gov: NCT00747721.

Figure 1

Structural formula of H-3 metabolite.

Figure 2

Dexmedetomidine concentration profiles of the 13 patients during the infusion and the 48-hour follow-up. The 48-hour follow-up was not reached in the three patients who were withdrawn from the study treatment and died of adverse events. Conc, concentration.

Figure 3

Dexmedetomidine concentration profiles during the 12-hour constant-rate infusion (n = 13) and the 48-hour follow-up after stopping the infusion (n = 10). The infusion rate was 0.7 μg/kg/h in all but one patient, who received dexmedetomidine, 0.1 μg/kg/h (dashed line), during the constant-rate phase. Conc, concentration.

Figure 4

Dexmedetomidine clearance at 116 steady states defined by a 15-hour constant-rate infusion in 12 subjects. Open triangles, open circles, and solid circles indicate an infusion rate of 0.1, 0.4 to 2.1, and 2.5 μg/kg/h, respectively. Each line represents one patient. In two patients, only one steady state was achieved, and the corresponding clearances are depicted with a single symbol.

Figure 5

Relation of the total dexmedetomidine dose and the area under the dexmedetomidine concentration-time curve extrapolated to infinity (AUC). The dashed lines represent the 95% confidence intervals for the regression line (solid line).

Figure 6

Success in reaching the target Richmond Agitation-Sedation Scale.