The potential for protein binding displacement of dexmedetomidine by fentanyl, ketorolac, theophylline, digoxin and lidocaine was explored in vitro, and negligible changes in the plasma protein binding of dexmedetomidine were observed. The potential for protein binding displacement of phenytoin, warfarin, ibuprofen, propranolol, theophylline and digoxin by dexmedetomidine was explored in vitro and none of these compounds appeared to be significantly displaced by dexmedetomidine.

Metabolism

Dexmedetomidine undergoes almost complete biotransformation with very little unchanged dexmedetomidine excreted in urine and feces. Biotransformation involves both direct glucuronidation as well as cytochrome P450 mediated metabolism. The major metabolic pathways of dexmedetomidine are: direct N-glucuronidation to inactive metabolites; aliphatic hydroxylation (mediated primarily by CYP2A6) of dexmedetomidine to generate 3-hydroxy dexmedetomidine, the glucuronide of 3-hydroxy dexmedetomidine, and 3-carboxy dexmedetomidine; and N-methylation of dexmedetomidine to generate 3-hydroxy N-methyl dexmedetomidine, 3-carboxy N-methyl dexmedetomidine, and N-methyl O-glucuronide dexmedetomidine.

Elimination

The terminal elimination half-life (t_1/2) of dexmedetomidine is approximately 2 hours and clearance is estimated to be approximately 39 L/h. A mass balance study demonstrated that after nine days an average of 95% of the radioactivity, following IV administration of radiolabeled dexmedetomidine, was recovered in the urine and 4% in the feces. No unchanged dexmedetomidine was detected in the urine. Approximately 85% of the radioactivity recovered in the urine was excreted within 24 hours after the infusion. Fractionation of the radioactivity excreted in urine demonstrated that products of N-glucuronidation accounted for approximately 34% of the cumulative urinary excretion. In addition, aliphatic hydroxylation of parent drug to form 3-hydroxy dexmedetomidine, the glucuronide of 3-hydroxy dexmedetomidine, and 3-carboxylic acid dexmedetomidine together represented approximately 14% of the dose in urine. N-methylation of dexmedetomidine to form 3-hydroxy N-methyl dexmedetomidine, 3-carboxy N-methyl dexmedetomidine, and N-methyl O-glucuronide dexmedetomidine accounted for approximately 18% of the dose in urine. The N-Methyl metabolite itself was a minor circulating component and was undetected in urine. Approximately 28% of the urinary metabolites have not been identified.

Gender

There was no observed difference in dexmedetomidine pharmacokinetics due to gender.

Geriatrics

The pharmacokinetic profile of dexmedetomidine was not altered by age. There were no differences in the pharmacokinetics of dexmedetomidine in young (18 – 40 years), middle age (41 – 65 years), and elderly ( > 65 years) subjects.

Pediatrics

The pharmacokinetic profile of dexmedetomidine has not been studied in pediatric patients.

Renal Impairment

Dexmedetomidine pharmacokinetics (Cmax, Tmax, AUC, t_1/2, CL, and V_SS) were not significantly different in subjects with severe renal impairment (creatinine clearance: < 30 mL/min) compared to healthy subjects. However, the pharmacokinetics of the metabolites of dexmedetomidine have not been evaluated in patients with impaired renal function. Since the majority of metabolites are excreted in the urine, it is possible that the metabolites may accumulate upon long-term infusions in patients with impaired renal function. (See PRECAUTIONS, DOSAGE AND ADMINISTRATION).

Hepatic Impairment

In subjects with varying degrees of hepatic impairment (Child-Pugh Class A, B, or C), clearance values for dexmedetomidine were lower than in healthy subjects. The mean clearance values for subjects with mild, moderate, and severe hepatic impairment were 74%, 64% and 53% of those observed in the normal healthy subjects, respectively. Mean clearances for free drug were 59%, 51% and 32% of those observed in the normal healthy subjects, respectively.

Although Precedex® is dosed to effect, it may be necessary to consider dose reduction in patients with hepatic impairment (see PRECAUTIONS, Hepatic Impairment and DOSAGE AND ADMINISTRATION).

Clinical Trials

Bookmark this page: