Dexmedetomidine pharmacokinetics in pediatric intensive care - a pooled analysis

P>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%) l center dot h-1 center dot 70 kg-1, central volume of distribution (V1) 56.3 (61.3%) l center dot 70 kg-1, inter-compartment clearance (Q) 78.3 (37.0%) l center dot h-1 center dot 70 kg-1 and peripheral volume of distribution (V2) 69.0 (47.0%) l center dot 70 kg-1. Clearance maturation with age was described using the Hill equation. Clearance increases from 18.2 l center dot h-1 center dot 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 mu g center dot 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 center dot h-1 center dot 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.