Dexmedetomidine Clearance Decreases with Increasing Drug Exposure: Implications for Current Dosing Regimens and Target-controlled Infusion Models Assuming Linear Pharmacokinetics

Abstract

Background 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. Methods 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. Results 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. Conclusions 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. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

General Purpose Pharmacokinetic-Pharmacodynamic Models for Target-Controlled Infusion of Anaesthetic Drugs: A Narrative Review

“…The Hannivoort PK model performed better than previously published PK models in an initial prospective validation study, where patients received dexmedetomidine during spinal anaesthesia [27]. However, in a subsequent interaction study by Weerink et al, in which healthy volunteers received dexmedetomidine and remifentanil, the Hannivoort PK model performed well only up until targets < 3 ng mL −1 ; but for higher concentrations (which are rarely necessary in clinical practice) non-linear kinetics were suspected and confirmed by Alvarez-Jiminez et al in a closer analysis of both the Hannivoort and Weerink data [35][36][37].…”

What’s New in Intravenous Anaesthesia? New Hypnotics, New Models and New Applications

“…The Hannivoort-Colin model has a PD component for four different pharmacodynamic endpoints: BIS, the Modified Observer’s Assessment of Alertness/Sedation (MOAA/S) score, heartrate, and mean arterial pressure. It can be safely used for plasma targets up to 2 ng mL −1 because it assumes linear pharmacokinetics [ 77 ] but at higher plasma concentrations, the kinetics become non-linear, and may result in higher plasma concentrations than expected.…”

Elimination Clearance of Dexmedetomidine: Cross-examining What the Data Say

“…Since multiple studies have demonstrated that dexmedetomidine decreases cardiac output, 4,7,8 this source of nonlinearity needs to be considered. Instead of incorporating their cardiac output data in a pharmacokinetic model according to Equation 2 and letting these data speak, Alvarez-Jimenez et al 2 dealt with this potential confounding factor by omitting arterial dexmedetomidine concentrations during and immediately after dexmedetomidine infusion and then suggesting that incomplete intravascular mixing was not the reason for the observed nonlinear kinetics.…”

“…9,10 α-Adrenergic agonists, including dexmedetomidine, 7 have been shown to reduce splanchnic blood flow. 11,12 Thus, increasing dexmedetomidine concentrations could lead to reduced hepatic blood flow and decreased (i.e., nonstationary) dexmedetomidine clearance, producing the nonlinear pharmacokinetic behavior as reported by Alvarez-Jimenez et al 2 Why should we care whether the enzymes are saturated, cardiac output decreases, or hepatic blood flow is reduced as long as the equation that is invoked in the modeling process fits the data and can predict dexmedetomidine concentrations for target-controlled infusion rates? It matters greatly.…”

“…1 With pharmacokinetic modeling, stationarity is typically assumed (i.e., volumes and clearances do not vary for the duration of the study). In this issue of Anesthesiology, Alvarez-Jimenez et al 2 report data indicating that this assumption has most likely been violated for dexmedetomidine elimination clearance and suggest, in their title, that this finding has implications for dexmedetomidine dosing. We will therefore discuss three possible sources of this nonstationarity.…”