A Universal Pharmacokinetic Model for Dexmedetomidine in Children and Adults

Abstract

A universal pharmacokinetic model was developed from pooled paediatric and adult data (40.6 postmenstrual weeks, 70.8 years, 3.1-152 kg). A three-compartment pharmacokinetic model with first-order elimination was superior to a two-compartment model to describe these pooled dexmedetomidine data. Population parameter estimates (population parameter variability%) were clearance (CL) 0.9 L/min/70 kg (36); intercompartmental clearances (Q2) 1.68 L/min/70 kg (63); Q3 0.62 L/min/70 kg (90); volume of distribution in the central compartment (V1) 25.2 L/70 kg (103.9); rapidly equilibrating peripheral compartment (V2) 34.4 L/70 kg (41.8); slow equilibrating peripheral compartment (V3) 65.4 L/70 kg (62). Obesity was best described by fat-free mass for clearances and normal fat mass for volumes with a factor for fat mass (FfatV) of 0.293. Models describing dexmedetomidine pharmacokinetics in adults can be applied to children by accounting for size (allometry) and age (maturation). This universal dexmedetomidine model is applicable to a broad range of ages and weights: neonates through to obese adults. Lean body weight is a better size descriptor for dexmedetomidine clearance than total body weight. This parameter set could be programmed into target-controlled infusion pumps for use in a broad population.

Keywords: anaesthesia; children; dexmedetomidine; intravenous; obesity; pharmacodynamics; pharmacokinetics; target-controlled infusion; total intravenous anaesthesia (TIVA).

Figure 1

Prediction-corrected visual predictive check (PC-VPC) for dexmedetomidine pharmacokinetics using the model by Hannivoort [7] with observed dexmedetomidine plasma concentrations sought from Potts [19]. Plots show median (solid) and 90% intervals (dashed lines). The left-hand plot shows all prediction-corrected observed dexmedetomidine concentrations. Right-hand plot shows prediction-corrected percentiles (10%, 50%, and 90%) for observations (grey dashed lines) and predictions (red dashed lines) with 95% confidence intervals for prediction percentiles (median, pink shading; 5th and 95th blue shading).

Figure 2

Violin plot showing the distribution of age (years), fat-free mass (kg), weight (kg), and height (cm) in the pooled dexmedetomidine data used to develop the universal PK model. A box and whisker plot overlays the violins in blue.

Figure 3

Prediction-corrected visual predictive check (PC-VPC) for the universal dexmedetomidine PK model. Model developed using pooled paediatric [19] and adult [16,26] dexmedetomidine plasma concentrations. Plots show median (solid) and 90% intervals (dashed lines). The left-hand plot shows all prediction-corrected observed dexmedetomidine concentrations. Right-hand plot shows prediction-corrected percentiles (10%, 50%, and 90%) for observations (grey dashed lines) and predictions (red dashed lines) with 95% confidence intervals for prediction percentiles (median, pink shading; 5th and 95th blue shading).

Figure 4

Maturation of dexmedetomidine clearance when scaled using fat-free mass, determined from pooled published data.

Figure 5

Simulated per kilo (TBW) dexmedetomidine maintenance infusion rates to maintain plasma concentration of 1 mcg/L. Infusion rates are affected by the effects of maturation and size in metabolic clearance. Clearance in term neonates is 42% of adult values, reaching 80% by 3 years of age. Allometric relationships between size and clearance explain the decrease in infusion rates (mcg/kg/min) in patients older than 3 years.