A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Precedex Pharmacology, Pharmacokinetics, Studies, Metabolism - Dexmedetomidine hydrochloride
Precedex Pharmacology, Pharmacokinetics, Studies, Metabolism - Dexmedetomidine hydrochloride
CLINICAL PHARMACOLOGY
General
Dexmedetomidine is a relatively selective alpha2-adrenoceptor
agonist with sedative properties.Alpha2-selectivity was observed
in animals following slow intravenous (IV) infusion of low and medium doses
(10-300 mcg/kg). Both alpha1 and alpha2 activity
was observed following slow IV infusion of high doses (³1000
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).
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 kinetics in the dosage range
of 0.2 to 0.7 mg/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 mg/kg/hr (target concentration of 0.3 ng/mL)
for 12 and 24 hours, 0.33 mg/kg/hr (target concentration
of 0.6 ng/mL) for 24 hours, and 0.70 mg/kg/hr (target
concentration of 1.25 ng/mL) for 24 hours.
Table 1: Mean ± SD Pharmacokinetic Parameters.
|
Parameter
|
Loading Infusion (min)/Total infusion duration (hrs)
|
|
10 min/12 hrs
|
10 min/24hrs
|
10 min/24 hrs
|
35 min/24 hrs
|
|
Dexmedetomidine Target Concentration (ng/mL) /Dose
(mcg/kg/hr)
|
|
0.3/0.17
|
0.3/0.17
|
0.6/0.33
|
1.25/0.70
|
|
tl/2*, hour
|
1.78 ± 0.30
|
2.22 ± 0.59
|
2.23 ± 0.21
|
2.50 ± 0.61
|
|
CL, liter/hour
|
46.3 ± 8.3
|
43.1 ± 6.5
|
35.3 ± 6.8
|
36.5 ± 7.5
|
|
Vss, liter
|
88.7 ± 22.9
|
102.4 ± 20.3
|
93.6 ± 17.0
|
99.6 ± 17.8
|
|
Avg Css#, ng/mL
|
0.27 ± 0.05
|
0.27 ± 0.05
|
0.67 ± 0.10
|
1.37 ± 0.20
|
*Presented as harmonic mean and pseudo standard deviation.
#Avg Css = Average steady-state concentration of dexmedetomidine.
(2.5 - 9 hour samples for 12 hour infusion and 2.5 - 18 hour samples for 24
hour infusions.).
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 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.
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 biotransoformation
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 (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 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-glucoronidation
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, t1/2, CL,
and VSS) 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,
Geriatrics, 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
The safety and efficacy of PRECEDEX has been evaluated in two
randomized, double-blind, parallel-group, placebo-controlled multicenter clinical
trials in 754 patients being treated in a surgical intensive care unit (ICU).
All patients were initially intubated and received mechanical ventilation. These
trials evaluated the sedative properties of dexmedetomidine by comparing the
amount of rescue medication (midazolam in one trial and propofol in the second)
required to achieve a specified level of sedation (using the standardized Ramsay
sedation scale) between PRECEDEX and placebo from onset of treatment to extubation
or to a total treatment duration of 24 hours. The Ramsay Level of Sedation Scale
is displayed in Table 2.
Table 2: Ramsay Level of Sedation Scale
|
Clinical Score
|
Level of Sedation Achieved
|
|
6
|
Asleep, no response
|
|
5
|
Asleep, sluggish response to light glabellar tap or loud auditory stimulus
|
|
4
|
Asleep, but with brisk response to light glabellar tap
or loud auditory stimulus
|
|
3
|
Patient responds to commands
|
|
2
|
Patient cooperative, oriented, and tranquil
|
|
1
|
Patient anxious, agitated, or restless
|
In the first study, 175 patients were randomized to receive
placebo and 178 to receive dexmedetomidine by intravenous infusion at a dose
of 0.4 mcg/kg/hr (with allowed adjustment between 0.2 and 0.7 mcg/kg/hr) following
an initial loading infusion of 1 (one) mcg/kg over 10 minutes. The study drug
infusion rate was adjusted to maintain a Ramsay sedation score of ³3.
Patients were allowed to receive "rescue" midazolam as needed to augment
the study drug infusion. In addition, morphine sulfate was administered for
pain as needed. The primary outcome measure for this study was the total amount
of rescue medication (midazolam) needed to maintain sedation as specified while
intubated. Patients randomized to placebo received significantly more midazolam
than patients randomized to dexmedetomidine (see Table 3).
A second prospective primary analysis assessed the sedative
effects of dexmedetomidine by comparing the percentage of patients who achieved
a Ramsay sedation score of ³3 during intubation without
the use of additional rescue medication. A significantly greater percentage
of patients in the dexmedetomidine group maintained a Ramsay sedation score
of ³3 without receiving any midazolam rescue compared
to the placebo group (see Table 3).
Table 3: Midazolam Use As Rescue Medication During Intubation
(ITT)* Study One
|
|
Placebo N=175
|
Dexmedetomidine N=178
|
p-value
|
|
Mean total dose of midazolam
|
19 mg
|
5 mg
|
0.0011**
|
|
Standard deviation
|
53 mg
|
19 mg
|
|
|
Categorized midazolam use
|
|
0mg
|
43(25%)
|
108 (61%)
|
<0.001***
|
|
0-4 mg
|
34 (19%)
|
36(20%)
|
|
|
>4 mg
|
98 (56%)
|
34 (19%)
|
|
*ITT (intent-to-treat) population includes all randomized patients.
**ANOVA model with treatment and Center
***Chi-Square
A prospective secondary analysis assessed the dose of morphine
sulfate administered to patients in the dexmedetomidine and placebo groups.
On average, dexmedetomidine-treated patients received less morphine sulfate
for pain than placebo-treated patients (0.47 versus 0.83 mg/h). In addition
44% (79 of 178 patients) of dexmedetomidine patients received no morphine sulfate
for pain versus 19% (33 of 175 patients) in the placebo group.
In a second study, 198 patients were randomized to receive
placebo and 203 to receive dexmedetomidine by intravenous infusion at a dose
of 0.4 mcg/kg/hr (with allowed adjustment between 0.2 and 0.7 mcg /kg/hr) following
an initial loading infusion of 1 (one) mcg/kg IV over 10 minutes. The study
drug infusion was adjusted to maintain a Ramsay sedation score of ³3.
Patients were allowed to receive "rescue" propofol as needed to augment
the study drug infusion. In addition, morphine sulfate was administered as needed
for pain. The primary outcome measure for this study was the total amount of
rescue medication (propofol) needed to maintain sedation as specified while
intubated. Patients randomized to placebo received significantly more propofol
than patients randomized to dexmedetomidine (see Table 4).
A significantly greater percentage of patients in the dexmedetomidine
group compared to the placebo group maintained a Ramsay sedation score of ³3
without receiving any propofol rescue (see Table 4).
Table 4: Propofol Use As Rescue Medication During Intubation
(ITT) Study Two
|
|
Placebo N=198
|
Dexmedetomidine N=203
|
p-value
|
|
Mean total dose (mg) of propofol
|
513 mg
|
72 mg
|
<0.0001*
|
|
Standard deviation
|
782 mg
|
249 mg
|
|
|
Categorized propofol use
|
|
0mg
|
47(24%)
|
122 (60%)
|
<0.001**
|
|
0-50 mg
|
30 (15%)
|
43 (21%)
|
|
|
>50 mg
|
121 (61%)
|
38 (19%)
|
|
*ANOVA model with treatment and center
**Chi-square
A prospective secondary analysis assessed the dose of morphine
sulfate administered to patients in the dexmedetomidine and placebo groups.
On average, dexmedetomidine-treated patients received less morphine sulfate
for pain than placebo-treated patients (0.43 versus 0.89 mg/h). In addition
41% (83 of 203 patients) of dexmedetomidine patients received no morphine sulfate
for pain versus 15% (30 of 198 patients) in the placebo group.
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