Population Pharmacokinetics of Dexmedetomidine in Critically Ill Patients

Abstract

Background and ObjectivesAlthough the pharmacokinetics of dexmedetomidine in healthy volunteers have been studied, there are limited data about the pharmacokinetics of long-term administration of dexmedetomidine in critically ill patients.MethodsThis population pharmacokinetic analysis was performed to quantify the pharmacokinetics of dexmedetomidine in critically ill patients following infusions up to 14 days in duration. The data consisted of three phase III studies (527 patients with sparse blood sampling, for a total of 2,144 samples). Covariates were included in a full random-effects covariate model and the most important covariate relationships were tested separately. The linearity of dexmedetomidine clearance was evaluated by observing steady-state plasma concentrations acquired at various infusion rates.ResultsThe data were adequately described with a one-compartment model. The clearance of dexmedetomidine was 39 (95 % CI 37–41) L/h and volume of distribution 104 (95 % CI 93–115) L. Both clearance and volume of distribution were highly variable between patients (coefficients of variation of 62 and 57 %, respectively), which highlights the importance of dose titration by response. Covariate analysis showed a strong correlation between body weight and clearance of dexmedetomidine. The clearance of dexmedetomidine was constant in the dose range 0.2–1.4 μg/kg/h.ConclusionsThe pharmacokinetics of dexmedetomidine are dose-proportional in prolonged infusions when dosing rates of 0.2–1.4 μg/kg/h, recommended by the Dexdor® summary of product characteristics, are used.

The Effect of Obesity on Dose of Dexmedetomidine When Administered With Fentanyl During Postoperative Mechanical Ventilation - Retrospective

“…Dyck et al built a pharmacokinetic model of DEX which included height as a covariate for central clearance in non -obese (mean body weight of 82 kg) adult volunteers 10) . Valitalo et al 11) performed a population pharmacokinetic analysis of DEX in critically ill patients in the intensive care unit (ICU) and found that TBW strongly correlates to clearance, and their final model included a TBW covariate on clearance. Because the formula structure that they used was based on the allometric scaling technique which is frequently used for pharmacokinetic analysis of anesthetics in obese patients 12) , the increase in clearance with body weight was at an exponential rate.…”

Development of an Optimized Pharmacokinetic Model of Dexmedetomidine Using Target-controlled Infusion in Healthy Volunteers

“…Figure 3 confirms this, as only in the highest concentrations (sparse data), the precision decreases and bias increases. Figure 5 shows the population predictions versus time and observed concentrations for previously published dexmedetomidine pharmacokinetic models, 4,[6][7][8][9][10] showing poorer fits for all models compared with our final model. Also, as seen in the C obs /C pred versus time graphs in figures 3 and 5, our model predicts initial concentrations more accurately than the existing models, indicating that the accuracy concerning front-end kinetics is acceptable.…”

“…Most of the existing pharmacokinetic models for dexmedetomidine were obtained from trials involving postoperative and/or ICU patients, using either computer-controlled infusion with an unpublished model 7 or continuous infusion. [8][9][10] This approach is sensitive to the influence of confounding drugs such as subtherapeutic levels of anesthetic drugs, additional sedation or analgesia, and other medications. The resulting pharmacokinetic models are thus less applicable to single drug pharmacokinetic modeling.…”

Dexmedetomidine: A Review of Its Use for Sedation in the Intensive Care Setting

“…Intravenous dexmedetomidine 0.2-1.4 lg/kg/h demonstrated linear pharmacokinetics [4,31], and no accumulation was seen when dexmedetomidine was infused for up to 14 days [4]. Dexmedetomidine pharmacokinetics were adequately described by a two-compartment disposition model [4,20,32].…”

“…The pharmacokinetics of dexmedetomidine were not altered to a clinically relevant extent based on age or gender or in patients with severe renal impairment [4,33], and no dosage adjustment is needed in the elderly or in patients with renal impairment [4]. Population pharmacokinetic analysis suggested a strong correlation between bodyweight and the clearance of dexmedetomidine [31]. Race did not appear to affect the pharmacokinetics of dexmedetomidine, with no significant differences seen between Caucasian and South Korean or Japanese subjects [7,34].…”