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.
Potts
Amanda L
AL
Department of Anaesthesiology, University of Auckland, Auckland, New Zealand. a.potts@auckland.ac.nz
Anderson
Brian J
BJ
Warman
Guy R
GR
Lerman
Jerrold
J
Diaz
Susan M
SM
Vilo
Sanna
S
D000293:Adolescent; D000316:Adrenergic alpha-Agonists / Q000493:pharmacokinetics*; D000367:Age Factors; D001810:Blood Volume; D002648:Child; D002675:Child, Preschool; D020927:Dexmedetomidine / Q000493:pharmacokinetics*; D054796:Drug Dosage Calculations; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D015278:Intensive Care Units, Pediatric; D008657:Metabolic Clearance Rate; D008954:Models, Biological
D000316:Adrenergic alpha-Agonists; D020927:Dexmedetomidine