title: Development of an Optimized Pharmacokinetic Model of Dexmedetomidine Using Target-controlled Infusion in Healthy Volunteers.
abstract: BACKGROUND
  Several pharmacokinetic models are available for dexmedetomidine, but these have been shown to underestimate plasma concentrations. Most were developed with data from patients during the postoperative phase and/or in intensive care, making them susceptible to errors due to drug interactions. The aim of this study is to improve on existing models using data from healthy volunteers.
  
  
  METHODS
  After local ethics committee approval, the authors recruited 18 volunteers, who received a dexmedetomidine target-controlled infusion with increasing target concentrations: 1, 2, 3, 4, 6, and 8 ng/ml, repeated in two sessions, at least 1 week apart. Each level was maintained for 30 min. If one of the predefined safety criteria was breached, the infusion was terminated and the recovery period began. Arterial blood samples were collected at preset times, and NONMEM (Icon plc, Ireland) was used for model development.
  
  
  RESULTS
  The age, weight, and body mass index ranges of the 18 volunteers (9 male and 9 female) were 20 to 70 yr, 51 to 110 kg, and 20.6 to 29.3 kg/m, respectively. A three-compartment allometric model was developed, with the following estimated parameters for an individual of 70 kg: V1 = 1.78 l, V2 = 30.3 l, V3 = 52.0 l, CL = 0.686 l/min, Q2 = 2.98 l/min, and Q3 = 0.602 l/min. The predictive performance as calculated by the median absolute performance error and median performance error was better than that of existing models.
  
  
  CONCLUSIONS
  Using target-controlled infusion in healthy volunteers, the pharmacokinetics of dexmedetomidine were best described by a three-compartment allometric model. Apart from weight, no other covariates were identified.
authors.affiliation: From the Department of Anesthesiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Laura N
authors.initials: LN
authors.lastname: Hannivoort
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Eleveld
authors.forename: Johannes H
authors.initials: JH
authors.lastname: Proost
authors.forename: Koen M E M
authors.initials: KM
authors.lastname: Reyntjens
authors.forename: Anthony R
authors.initials: AR
authors.lastname: Absalom
authors.forename: Hugo E M
authors.initials: HE
authors.lastname: Vereecke
authors.forename: Michel M R F
authors.initials: MM
authors.lastname: Struys
mesh_terms: D000328:Adult; D000368:Aged; D018686:Anesthetics, Intravenous / Q000008:administration & dosage / Q000493:pharmacokinetics*; D020927:Dexmedetomidine / Q000493:pharmacokinetics*; D016503:Drug Delivery Systems / Q000379:methods*; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D055815:Young Adult
chemical_list: D018686:Anesthetics, Intravenous; D020927:Dexmedetomidine