Population Modelling of Dexmedetomidine Pharmacokinetics and Haemodynamic Effects After Intravenous and Subcutaneous Administration

Abstract

Background and objective: Dexmedetomidine is a potent agonist of α2-adrenoceptors causing dose-dependent sedation in humans. Intravenous dexmedetomidine is commonly used perioperatively, but an extravascular route of administration would be favoured in palliative care. Subcutaneous infusions provide desired therapeutic plasma concentrations with fewer unwanted effects as compared with intravenous dosing. We aimed to develop semi-mechanistic population models for predicting pharmacokinetic and pharmacodynamic profiles of dexmedetomidine after intravenous and subcutaneous dosing.

Methods: Non-linear mixed-effects modelling was performed using previously collected concentration and haemodynamic effects data from ten (eight in the intravenous phase) healthy human subjects, aged 19-27 years, receiving 1 µg/kg of intravenous or subcutaneous dexmedetomidine during a 10-min infusion.

Results: The absorption of dexmedetomidine from the subcutaneous injection site, and distribution to local subcutaneous fat tissue was modelled using a semi-physiological approach consisting of a depot and fat compartment, while a two-compartment mammillary model explained further disposition. Dexmedetomidine-induced reductions in plasma norepinephrine concentrations were accurately described by an indirect response model. For blood pressure models, the net effect was specified as hyper- and hypotensive effects of dexmedetomidine due to vasoconstriction on peripheral arteries and sympatholysis mediated via the central nervous system, respectively. A heart rate model combined the dexmedetomidine-induced sympatholytic effect, and input from the central nervous system, predicted from arterial blood pressure levels. Internal evaluation confirmed the predictive performance of the final models, as well as the accuracy of the parameter estimates with narrow confidence intervals.

Conclusions: Our final model precisely describes dexmedetomidine pharmacokinetics and accurately predicts dexmedetomidine-induced sympatholysis and other pharmacodynamic effects. After subcutaneous dosing, dexmedetomidine is taken up into subcutaneous fat tissue, but our simulations indicate that accumulation of dexmedetomidine in this compartment is insignificant. CLINICALTRIALS.ORG: NCT02724098 and EudraCT 2015-004698-34.

Conflict of interest statement

MWA, PU and TIS received a speaker honorarium from Orion Pharma Ltd (Espoo, Finland). MS had contract research relationships with Orion Corporation Ltd (Espoo, Finland), Novartis Pharma (Espoo, Finland), Desentum Ltd (Helsinki, Finland), Gabather AB (Gothenburg, Sweden), AbbVie AG (Germany) and AC Immune SA (Lausanne, Switzerland). In addition, MS has received fees for participation on Data and Safety Committees in Faron Pharmaceuticals (Turku, Finland) and Herantis Pharma (Helsinki, Finland). MS has received a speaker’s fee from Pharma Industry Finland (Helsinki, Finland) and he has stock options for Santhera Pharmaceuticals (Pratteln, Switzerland).

Figures

Fig. 1

Schematic of the final semi-mechanistic model for dexmedetomidine pharmacokinetics (a), its effect on norepinephrine (NE) release (b), systolic and diastolic blood pressures (c), and heart rate (d). A amount, C1 dexmedetomidine concentration on central compartment, CE amount of (heart rate/systolic or diastolic blood pressure), CNS central nervous system, EC effect compartment, EC50 concentration causing 50% effect from EMAX, EMAX maximum effect, Fspill fraction on NE spilled out from the release compartment, HPN hypotension, HR heart rate, HTN hypertension, I(t) dosing event, IV intravenous, k1e, k5e and k7e rate constants for distribution to the effect compartment, kIN,R rate constant for NE release, ka absorption rate constant, ke0 elimination rate constant for the effect, kOUT,P rate constant for NE elimination from the plasma, P plasma, R release, SC subcutaneous, γ hill parameter

Fig. 2

Visual predictive checks based on 1000 simulations showing dexmedetomidine and norepinephrine after a 1-µg/kg intravenous (a, c) or subcutaneous (b, d) dexmedetomidine infusion. The black solid and dashed lines are the observed percentiles (10th, 50th and 90th percentiles) respectively, and the blue ribbon is the corresponding median predictive interval. Light blue ribbons are predicted percentiles. Black circles are individual observations

Fig. 3

Visual predictive checks based on 1000 simulations showing heart rate (upper row), systolic blood pressure (middle row) and diastolic blood pressure (lower row) after a 1-µg/kg intravenous (a, c, e) or subcutaneous (b, d, f) dexmedetomidine infusion. The black solid and dashed lines are the observed percentiles (10th, 50th, and 90th percentiles), respectively, and the blue ribbon is the corresponding median predictive interval. Light blue ribbons are predicted percentiles. Black circles are individual observations

Fig. 4

Simulated dexmedetomidine concentration profiles in plasma using the final mechanism-based model and 8-h (upper row) and 48-h (lower row) intravenous (a, c) and subcutaneous (b, d) continuous infusions of varying dexmedetomidine doses

Fig. 5

Simulated norepinephrine concentration profiles in plasma using the final mechanism-based model and 8-h (upper row) and 48-h (lower row) intravenous (a, c) and subcutaneous (b, d) continuous infusions of varying dexmedetomidine doses