General

Dexmedetomidine is a relatively selective alpha₂-adrenoceptor agonist with sedative properties. Alpha2 selectivity is observed in animals following slow Intravenous (IV) infusion of low and medium doses (10-300 mcg/kg). Both alpha₁ and alpha₂ activity is observed following slow IV infusion of high doses ( ≥ 1000 mcg/kg) or with rapid IV administration.

In a study in healthy volunteers (N=10), respiratory rate and oxygen saturation remained within normal limits and there was no evidence of respiratory depression when Precedex® was administered by IV infusion at doses within the recommended dose range (0.2 – 0.7 mcg/kg/hr).

Pharmacokinetics

Following intravenous administration, dexmedetomidine exhibits the following pharmacokinetic parameters: a rapid distribution phase with a distribution half-life (t_1/2) of approximately 6 minutes; a terminal elimination half-life (t_1/2) of approximately 2 hours; and steady-state volume of distribution (V_ss) of approximately 118 liters. Clearance is estimated to be approximately 39 L/h. The mean body weight associated with this clearance estimate was 72 kg.

Dexmedetomidine exhibits linear kinetics in the dosage range of 0.2 to 0.7 µg/kg/hr when administered by IV infusion for up to 24 hours. Table 1 shows the main pharmacokinetic parameters when Precedex® was infused (after appropriate loading doses) at maintenance infusion rates of 0.17 µg/kg/hr (target concentration of 0.3 ng/mL) for 12 and 24 hours, 0.33 µg/kg/hr (target concentration of 0.6 ng/mL) for 24 hours, and 0.70 µg/kg/hr (target concentration of 1.25 ng/mL) for 24 hours.

Table 1: Mean ± SD Pharmacokinetic Parameters

Distribution

The steady-state volume of distribution (V_ss) of dexmedetomidine is approximately 118 liters. Dexmedetomidine protein binding was assessed in the plasma of normal healthy male and female volunteers. The average protein binding was 94% and was constant across the different concentrations tested. Protein binding was similar in males and females. The fraction of dexmedetomidine that was bound to plasma proteins was statistically significantly decreased in subjects with hepatic impairment compared to healthy subjects.

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