Pharmacokinetics of dexmedetomidine during analgosedation in ICU patients

Abstract

Dexmedetomidine (DEX) is a fairly new alfa₂-agonist which has been increasingly used in recent years for analgosedation, mostly because it offers a unique ability of providing both moderate level of sedation and analgesia without respiratory depression. Despite of many papers published, there are still only a few concerning the PK of the drug given as long-term infusion in ICU patients. The aim of this work was to characterize the population pharmacokinetics of dexmedetomidine and to investigate the potential benefits of individualization of drug dosing based on patient characteristics in the heterogeneous group of medical and surgical patients staying in intensive care unit. This study was performed in the group of 17 males and 10 females patients with a median age of 59.5 years and median body weight of 75 kg. Blood samples for dexmedetomidine assay were collected from arterial catheter, during and after discontinuation of a standard infusion, that ranged from 24 to 102 h. The following covariates were examined to influence dexmedetomidine PK: age, sex, body weight, patients' health status described by Sequential Organ Failure Assessment Score (SOFA), inotropes usage, and infusion duration. The dexmedetomidine PK was best described by a two-compartment model. The typical values of PK parameters were estimated as 27 L for the volume of the central compartment, 87.6 L for the volume of the peripheral compartment, 38.5 L/h (9.2 mL/min/kg for a 70 kg patient) for systemic clearance and 46.4 L/h for the distribution clearance. Those values are consistent with literature findings. We were unable to show any significant relationship between collected covariates and dexmedetomidine PK. This study does not provide sufficient evidence to support the individualization of dexmedetomidine dosing based on age, sex, body weight, SOFA, and infusion duration.

Keywords: Dexmedetomidine; ICU; Pharmacokinetic; Sedation.

Fig. 1

The individual dexmedetomidine concentration–time profiles

Fig. 2

The prediction-corrected VPC plots for dexmedetomidine PK. The VPC plots show the simulation-based 95% confidence intervals around the 10th, 50th, and 90th percentiles of the PK data in the form of blue (50th) and gray (10th and 90th) areas. The corresponding percentiles from the prediction corrected observed data are plotted in black color

Fig. 3

Relationship between body weight normalized clearance and volume of distribution at steady state versus age, body weight, infusion duration and sex for all patients in the study