Numerous pharmacokinetic models have been published aiming at more accurate and safer dosing of dexmedetomidine. The vast majority of the developed models underpredict the measured plasma concentrations with respect to the target concentration, especially at plasma concentrations higher than those used in the original studies. The aim of this article was to develop a dexmedetomidine pharmacokinetic model in healthy adults emphasizing linear versus nonlinear kinetics.
The data of two previously published clinical trials with stepwise increasing dexmedetomidine target-controlled infusion were pooled to build a pharmacokinetic model using the NONMEM software package (ICON Development Solutions, USA). Data from 48 healthy subjects, included in a stratified manner, were utilized to build the model.
A three-compartment mamillary model with nonlinear elimination from the central compartment was superior to a model assuming linear pharmacokinetics. Covariates included in the final model were age, sex, and total body weight. Cardiac output did not explain between-subject or within-subject variability in dexmedetomidine clearance. The results of a simulation study based on the final model showed that at concentrations up to 2 ng · ml–1, the predicted dexmedetomidine plasma concentrations were similar between the currently available Hannivoort model assuming linear pharmacokinetics and the nonlinear model developed in this study. At higher simulated plasma concentrations, exposure increased nonlinearly with target concentration due to the decreasing dexmedetomidine clearance with increasing plasma concentrations. Simulations also show that currently approved dosing regimens in the intensive care unit may potentially lead to higher-than-expected dexmedetomidine plasma concentrations.
This study developed a nonlinear three-compartment pharmacokinetic model that accurately described dexmedetomidine plasma concentrations. Dexmedetomidine may be safely administered up to target-controlled infusion targets under 2 ng · ml–1 using the Hannivoort model, which assumed linear pharmacokinetics. Consideration should be taken during long-term administration and during an initial loading dose when following the dosing strategies of the current guidelines.
- Dexmedetomidine pharmacokinetic models underpredict the measured plasma target-controlled infusion concentrations that are higher than those used in the model validation studies
- The elimination clearance of high hepatic extraction ratio drugs like dexmedetomidine is determined by liver blood flow and not enzyme activity
- The data of 48 subjects from two published pharmacokinetic studies were pooled to build a three-compartment pharmacokinetic model with nonlinear elimination clearance that successfully predicted plasma dexmedetomidine concentrations over a wide concentration range
- Cardiac output did not explain between-subject or within-subject variability in dexmedetomidine elimination clearance
- Dexmedetomidine elimination clearance may decrease with increasing plasma concentrations because it alters the liver blood flow–to–cardiac output ratio in a concentration-dependent manner