Investigation of intranasal dexmedetomidine : pharmacokinetic-pharmacodynamic characteristics and formulation

Abstract

Dexmedetomidine is a highly potent alpha-2 adrenoceptor agonist. It induces sedative, analgesic, and hemodynamic changes. Following its approval by the US Food and Drug Administration (FDA) in 1999, dexmedetomidine has been used in different clinical procedures and demonstrated its sedation efficacy after both intravenous and extravascular administration. Intranasal dexmedetomidine produces safe, effective sedation in children and adults. It is an attractive and promising alternative of intravenous dexmedetomidine due to the non-invasive and convenient nature.

A prospective, three-period, crossover, double-blind study in eight healthy volunteers was performed to compare the pharmacokinetic and pharmacodynamic profile of dexmedetomidine after intravenous and two different modes of intranasal administration. In each session, each subject received 1 μg/kg dexmedetomidine either through intravenous infusion using programmable syringe pump, intranasal by drops using needle-free syringe, or intranasal by atomization using Mucosal Atomization Device (MAD^TM).

A bioanalytical method using liquid-liquid extraction for sample preparation and ultra-performance liquid chromatography-tandem mass spectrometry for separation and detection was developed and validated for quantification of dexmedetomidine in human plasma. Almost identical pharmacokinetic profiles after intranasal by drops and intranasal by atomization administration were observed. Population pharmacokinetic (PK) model were developed to characterize the pharmacokinetic profile and absorption pattern. The final PK model consisted of three parts: i) a 2-compartment model as the structural model; ii) a well-stirred model describing how change in heart rate affected central clearance; and iii) a transit compartment model describing the absorption process after intranasal administration. Decreased heart rate as a consequence of high plasma level of dexmedetomidine, would lead to decrease in cardiac output, followed by decrease in hepatic blood flow then clearance. Intranasal bioavailability was 40.7% and 40.6% for dripping and atomization respectively. No significant difference in PK parameters was identified between the two modes of intranasal administration.

A population pharmacodynamic (PD) model was sequentially developed to quantitatively assess the drug exposure-sedation effect relationship. Ramsay sedation score as a PD endpoint was modelled as an ordered categorical variable via a sigmoidal Emax model driven by an effect compartment. Adding a first order Markov model improved predictions (P<0.05). The effect compartment showed rapid equilibration with equilibrating rate constant 12.6 h^(-1), and the EC50 was estimated to be 903 pg/mL. Visual predictive check demonstrated that probability of each sedation score level over time was well predicted. There was no significant difference in PD characteristics between two modes of intranasal administration either.

Besides, in order to minimize the drainage of drug solution from nostril during intranasal administration, feasibility of mucoadhesive formulations were investigated. Biocompatible polymers Carbopol^® 974P NF, Pluronic^® F127, and HPMC^® 60SH50 were used to prepare mucoadhesive formulations of dexmedetomidine with wide range of viscosity. The drug was found stable in long-term and short-term stability study in presence of these polymers. 1%, 2% HPMC and 0.1%, 0.25% Carbopol showed minimal effect on drug permeability across Calu-3 cell layer in in vitro permeability study.