CLINICAL PHARMACOLOGY
Mechanism of Action
Precedex is a relatively selective alpha2-adrenergic agonist with sedative properties. Alpha2 selectivity is observed in animals following slow intravenous infusion of low and medium doses (10-300 mcg/kg). Both alpha1 and alpha2 activity is observed following slow intravenous infusion of high doses (≥1000 mcg/kg) or with rapid intravenous administration.
Pharmacodynamics
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 intravenous 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 (t1/2) of approximately 6 minutes; a terminal elimination half-life (t1/2) of approximately 2 hours; and steady-state volume of distribution (Vss) 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 pharmacokinetics in the dosage range of 0.2 to 0.7 mcg/kg/hr when administered by intravenous infusion for up to 24 hours. Table 5 shows the main pharmacokinetic parameters when Precedex was infused (after appropriate loading doses) at maintenance infusion rates of 0.17 mcg/kg/hr (target plasma concentration of 0.3 ng/mL) for 12 and 24 hours, 0.33 mcg/kg/hr (target plasma concentration of 0.6 ng/mL) for 24 hours, and 0.70 mcg/kg/hr (target plasma concentration of 1.25 ng/mL) for 24 hours.
Table 5: Mean ± SD Pharmacokinetic Parameters Parameter | Loading Infusion (min)/Total Infusion Duration (hrs) |
| 10 min/12 hrs | 10 min/24 hrs | 10 min/24 hrs | 35 min/24 hrs |
| Precedex Target Plasma Concentration (ng/mL) and Dose (mcg/kg/hr) |
| 0.3/0.17 | 0.3/0.17 | 0.6/0.33 | 1.25/0.70 |
* Presented as harmonic mean and pseudo standard deviation.
# Avg Css = Average steady-state concentration of Precedex. (2.5−9 hour samples for 12 hour infusion and 2.5−18 hour samples for 24 hour infusions).
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t 1/2 *, hour
CL, liter/hour
Vss, liter
Avg Css #, ng/mL
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1.78 ± 0.30
46.3 ± 8.3
88.7 ± 22.9
0.27 ± 0.05
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2.22 ± 0.59
43.1 ± 6.5
102.4 ± 20.3
0.27 ± 0.05
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2.23 ± 0.21
35.3 ± 6.8
93.6 ± 17.0
0.67 ± 0.10
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2.50 ± 0.61
36.5 ± 7.5
99.6 ± 17.8
1.37 ± 0.20
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Distribution
The steady-state volume of distribution (Vss) of dexmedetomidine is approximately 118 liters. Dexmedetomidine protein binding was assessed in the plasma of normal healthy male and female subjects. The average protein binding was 94% and was constant across the different plasma concentrations tested. Protein binding was similar in males and females. The fraction of Precedex that was bound to plasma proteins was significantly decreased in subjects with hepatic impairment compared to healthy subjects.
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 Precedex were observed. The potential for protein binding displacement of phenytoin, warfarin, ibuprofen, propranolol, theophylline and digoxin by Precedex was explored in vitro and none of these compounds appeared to be significantly displaced by Precedex.
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 dexmedetomidine-N-methyl O-glucuronide.
Elimination
The terminal elimination half-life (t1/2) 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 intravenous 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 Precedex pharmacokinetics due to gender.
Geriatrics:
The pharmacokinetic profile of Precedex was not altered by age. There were no differences in the pharmacokinetics of Precedex in young (18–40 years), middle age (41–65 years), and elderly (>65 years) subjects.
Pediatrics:
The pharmacokinetic profile of Precedex has not been studied in pediatric patients.
Hepatic Impairment:
In subjects with varying degrees of hepatic impairment (Child-Pugh Class A, B, or C), clearance values for Precedex were lower than in healthy subjects. The mean clearance values for patients 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 subjects with hepatic impairment [ see Dosage and Administration (2.2), Warnings and Precautions (5.6) ].
Renal Impairment:
Precedex pharmacokinetics (Cmax, Tmax, AUC, t1/2, CL, and Vss) were not significantly different in patients with severe renal impairment (creatinine clearance:<30 mL/min) compared to healthy subjects. However, the pharmacokinetics of the metabolites of Precedex 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 Dosage and Administration (2.2) and Use in Specific Populations (8.7) ].
Drug Interactions:
In vitro studies: In vitro studies in human liver microsomes demonstrated no evidence of cytochrome P450 mediated drug interactions that are likely to be of clinical relevance.
NONCLINICAL TOXICOLOGY
Carcinogenesis, Mutagenesis, Impairment of Fertility
Animal carcinogenicity studies have not been performed with Precedex.
Dexmedetomidine was not mutagenic in vitro, in either the bacterial reverse mutation assay (E. coli and Salmonella typhimurium) or the mammalian cell forward mutation assay (mouse lymphoma). Dexmedetomidine was clastogenic in the in vitro human lymphocyte chromosome aberration test with, but not without, rat S9 metabolic activation. In contrast, dexmedetomidine was not clastogenic in the in vitro human lymphocyte chromosome aberration test with or without human S9 metabolic activation. Although dexmedetomidine was clastogenic in an in vivo mouse micronucleus test in NMRI mice, there was no evidence of clastogenicity in CD-1 mice.
Fertility in male or female rats was not affected after daily subcutaneous injections at doses up to 54 mcg/kg (less than the maximum recommended human intravenous dose on a mcg/m2 basis). Precedex was dosed from 10 weeks prior to mating in males and 3 weeks prior to mating and during mating in females.
Animal Toxicology and/or Pharmacology
Dexmedetomidine had no effect on adrenocorticotropic hormone-stimulated cortisol release in dogs after a single dose; however, after the subcutaneous infusion of Precedex for one week, the cortisol response to adrenocorticotropic hormone was diminished by approximately 40%, indicating adrenal insufficiency.
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