Population Pharmacokinetic Model of Dexmedetomidine in a Heterogeneous Group of Patients

Dexmedetomidine is a hepatically eliminated drug with sedative, anxiolytic, sympatholytic, and analgesic properties that has been increasingly used for various indications in the form of a short or continuous intravenous infusion. This study aimed to propose a population pharmacokinetic (PK) model of dexmedetomidine in a heterogeneous group of intensive care unit patients, incorporating 29 covariates potentially linked with dexmedetomidine PK. Data were collected from 70 patients aged between 0.25 and 88 years and treated with dexmedetomidine infusion for various durations at 1 of 4 medical centers. Statistical analysis was performed using a nonlinear mixed-effect model. Categorical and continuous covariates including demographic data, hemodynamic parameters, biochemical markers, and 11 single-nucleotide polymorphisms were tested. A 2-compartment model was used to describe dexmedetomidine PK. An allometric/isometric scaling was used to account for body weight difference in PK parameters, and the Hill equation was used to describe the maturation of clearance. Typical values of the central and peripheral volume of distribution and the systemic and distribution clearance for a theoretical adult patient were central volume of distribution = 22.50 L, peripheral volume of distribution  = 86.1 L, systemic clearance =  34.7 L/h, and distribution clearance = 40.8 L/h. The CYP1A2 genetic polymorphism and noradrenaline administration were identified as significant covariates for clearance. A population PK model of dexmedetomidine was successfully developed. The proposed model is well calibrated to the observed data. The identified covariates account for <5% of interindividual variability and consequently are of low clinical significance for the purpose of dose adjustment.