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
Wellbutrin Pharmacology, Pharmacokinetics, Studies, Metabolism - Bupropion
Wellbutrin Pharmacology, Pharmacokinetics, Studies, Metabolism - Bupropion
CLINICAL PHARMACOLOGY
Pharmacodynamics and Pharmacological Actions
Pharmacodynamics:
Bupropion is a relatively weak inhibitor of the neuronal uptake of
norepinephrine, serotonin, and dopamine, and does not inhibit monoamine oxidase. The
mechanism by which ZYBAN enhances the ability of patients to abstain from smoking is
unknown. However, it is presumed that this action is mediated by noradrenergic and/or
dopaminergic mechanisms.
Pharmacokinetics:
Bupropion is a racemic mixture. The pharmacologic activity and
pharmacokinetics of the individual enantiomers have not been studied. Bupropion follows
biphasic pharmacokinetics best described by a 2-compartment model. The terminal phase has a mean
half-life (±% CV) of about 21 hours (±20%), while the distribution phase has a mean half-life of 3 to 4 hours.
Absorption
Bupropion has not been administered intravenously to humans; therefore,
the absolute bioavailability
of bupropion sustained-release
tablets in humans has not been determined. In
rat and dog studies, the bioavailability
of bupropion ranged from
5% to 20%.
Following oral administration
of bupropion sustained release
tablets to healthy volunteers, peak plasma
concentrations of bupropion
are achieved within 3 hours (2 hours for the immediate
release formulation). The
mean peak concentration
(Cmax) values for the sustained release
tablets were 91 and 143 ng/ml from two single-dose (150 mg) studies. At
steady state, the mean Cmax
following a 150 mg dose
every 12 hours is 136 ng/ml.
In a single-dose study, food
increased Cmax by 11% and the extent of absorption
as defined by area under the
plasma concentration-time curve
(AUC) of bupropion by 17%.
The mean time
to peak concentration
(Tmax) was prolonged by 1 hour. This effect
was of no clinical significance.
Distribution
In vitro tests wshow that
bupropion is 80% or more
bound to human albumin at plasma
concentrations up to 800 mcmol/L (200 mcg/ml).
The extent of protein binding
of the hydroxybupropion metabolite is similar to that for bupropion, whereas
the extent of protein binding
of the threohydrobupropion metabolite
is about half that seen with bupropion. The volume
of distribution for the
sustained release tablets
(Vss/F) estimated from a single 150-mg dose
given to 17 subjects is 1950 L (20% CV).
Metabolism
Bupropion is extensively metabolized in humans. There are three active
metabolites: hydroxybupropion and the amino-alcohol isomers threohydrobupropion
and erythrohydrobupropion, which are formed via
hydroxylation of the tert-butyl group of bupropion
and/or reduction of the
carbonyl group. Oxidation
of the bupropion side
chain results in the formation
of a glycine conjugate of
meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite.
The potency and toxicity of the metabolites relative to bupropion have
not been fully characterized; however, it has been demonstrated in mice
that hydroxybupropion is comparable in potency to bupropion, while the
other metabolites are one tenth to one half as potent. This may be of
clinical importance because
the plasma concentrations of
the metabolites are higher than those of bupropion. In vitro findings
suggest that cytochrome P450 2B6 (CYP2B6) is the principle
isoenzyme involved in the
formation of hydroxybupropion, which cytochrome
P450 isoenzymes are not involved in the formation
of threohydrobupropion.
Because bupropion is extensively
metabolized, there is the potential for drug-drug interactions, particularly
with those agents that are metabolized by the cytochrome
P450IIB6 (CYP2B6) isoenzyme. Although bupropion
is not metabolized by cytochrome
P450IID6 (CYP2D6), there is the potential
for drug-drug interactions when bupropion
is co-administered with drugs metabolozied by this isoenzyme
(see DRUG INTERACTIONS).
Following a single dose in humans,
peak plasma concentrations
of the morpholinol metabolite
(hydroxybupropion) occur approximately 6 hours after administration of
bupropion HCl sustained
release tablets. Peak plasma
concentrations of the morpholinol metabolite
are approximately 10 times the peak level of the parent
drug at steady state
with bupropion HCl sustained
release tablets. The elimination
half-life of the morpholinol
metabolite is approximately 20 (±5)
hours, and its AUC at steady state
is about 17 times that of bupropion. The times to peak concentrations
for the erythrohydrobuprobion and threohydrobupropion are similar to that
of the morpholinol metabolite. However, their elimination half-lives are
longer, 33 (±10) and 37 (±13)
hours, respectively, and steady-state AUCs are 1.5 and 7 times that of
bupropion.
In a study comparing chronic
dosing with bupropion HCl
sustained release tablets 150 mg
twice a day to the immediate
release formulation of bupropion
at 100 mg three times a day, peak
plasma concentrations of bupropion
at steady state for bupropion
HCl sustained release tablets
were approximately 85% of those achieved with the immediate-release formulation.
There was equivalence for both peak plasma
concentration and AUCs
for all three of the detectable bupropion
metabolites. Thus, at steady state, bupropion sustained release
tablets and the immediate-release formulation are essentially bioequivalent
for both bupropion and the
three quantitatively important metabolites.
Bupropion and its metabolites exhibit linear
kinetics following chronic
administration of 300 to 450 mg/day.
Elimination
The mean (±% CV) apparent clearance (Cl/F) estimated from 2 single-dose
(150-mg) studies are 135 (±20%) and 209 L/hr (±21%). Following chronic dosing of 150 mg of
ZYBAN every 12 hours for 14 days (n = 34), the mean Cl/F at steady state was 160 L/hr (±23%).
The mean elimination half-life of bupropion estimated from a series of studies is approximately
21 hours. Estimates of the half-lives of the metabolites determined from a multiple-dose study
were 20 hours (±25%) for hydroxybupropion, 37 hours (±35%) for threohydrobupropion, and
33 hours (±30%) for erythrohydrobupropion. Steady-state plasma concentrations of bupropion
and metabolites are reached within 5 and 8 days, respectively.
Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the
radioactive dose were recovered in the urine and feces, respectively. The fraction of the oral dose
of bupropion excreted unchanged was only 0.5%.
The effects of cigarette smoking on the pharmacokinetics of bupropion were studied in
34 healthy male and female volunteers; 17 were chronic cigarette smokers and 17 were
nonsmokers. Following oral administration of a single 150-mg dose of ZYBAN, there was no
statistically significant difference in Cmax, half-life, Tmax, AUC, or clearance of bupropion or its
major metabolites between smokers and nonsmokers.
In a study comparing the treatment combination of ZYBAN and nicotine transdermal system
(NTS) versus ZYBAN alone, no statistically significant differences were observed between the
2 treatment groups of combination ZYBAN and NTS (n = 197) and ZYBAN alone (n = 193) in
the plasma concentrations of bupropion or its active metabolites at weeks 3 and 6.
Population Subgroups:
Factors or conditions altering metabolic capacity (e.g., liver
disease, congestive heart failure,
age, concomitant medications,
etc.) or elimination may
be expected to influence the degree
and extent of accumulation of the active metabolites of bupropion. The
elimination of the major
metabolites of bupropion
may be affected by reduced renal
or hepatic function
because they are moderately polar
compounds and are likely to undergo further metabolism or conjugation
in the liver prior to urinary
excretion.
Hepatic:The effect of hepatic impairment on the pharmacokinetics of bupropion was
characterized in 2 single-dose studies, one in patients with alcoholic liver disease and one in
patients with mild to severe cirrhosis.
The first study showed that the half-life of hydroxybupropion was significantly longer in
8 patients with alcoholic liver disease than in 8 healthy volunteers (32±14 hours versus
21±5 hours, respectively). Although not statistically significant, the AUCs for bupropion and hydroxybupropion were more variable and tended to be greater (by 53% to 57%) in patients with
alcoholic liver disease. The differences in half-life for bupropion and the other metabolites in the
2 patient groups were minimal.
The second study showed that there were no statistically significant differences in the
pharmacokinetics of bupropion and its active metabolites in 9 patients with mild to moderate
hepatic cirrhosis compared to 8 healthy volunteers. However, more variability was observed in
some of the pharmacokinetic parameters for bupropion (AUC, Cmax, and Tmax) and its active
metabolites (t½) in patients with mild to moderate hepatic cirrhosis. In addition, in patients with
severe hepatic cirrhosis, the bupropion Cmax and AUC were substantially increased (mean
difference: by approximately 70% and 3-fold, respectively) and more variable when compared to
values in healthy volunteers; the mean bupropion half-life was also longer (29 hours in patients
with severe hepatic cirrhosis vs. 19 hours in healthy subjects). For the metabolite
hydroxybupropion, the mean Cmax was approximately 69% lower.
For the combined amino-alcohol isomers threohydrobupropion and erythrohydrobupropion,
the mean Cmax was approximately 31% lower. The mean AUC increased by 28% for
hydroxybupropion and 50% for threo/erythrohydrobupropion.
The median Tmax was observed 19 hours later for hydroxybupropion and 21 hours later for
threo/erythrohydrobupropion. The mean half-lives for hydroxybupropion and
threo/erythrohydrobupropion were increased 2- and 4-fold, respectively, in patients with severe
hepatic cirrhosis compared to healthy volunteers (see WARNINGS, PRECAUTIONS, and
DOSAGE AND ADMINISTRATION).
Renal: The effect
of renal disease
on the pharmacokinetics of bupropion
has not been studied. The elimination
of the major metabolites of bupropion
may be affected by reduced renal
function.
Left Ventricular Dysfunction: During a chronic dosing study with bupropion in
14 depressed patients with left ventricular dysfunction (history of congestive heart failure [CHF]
or an enlarged heart on x-ray), no apparent effect on the pharmacokinetics of bupropion or its
metabolites, compared to healthy normal volunteers, was revealed.
Age: The effects of age
on the pharmacokinetics
of bupropion and its metabolites have not been fully characterized, but
an exploration of steady-state bupropion
concentrations from several efficacy studies involving patients dosed
in a range of 300 to 750 mg/day,
on a three-times daily schedule, revealed no relationship between age
(18 to 83 years) and plasma concentration
of bupropion. A single-dose pharmacokinetic study demonstrated that the
disposition of bupropion
and its metabolites in elderly subjects was similar to that of younger
subjects. These data suggest there is no prominent effect
of age on bupropion
concentration; however, another pharmacokinetic study, single and multiple
dose, has suggested that the elderly are at increased risk
for accumulation of bupropion
and its metabolites (see PRECAUTIONS,
Geriatric Use).
Gender: A single-dose study involving 12 healthy male and
12 healthy female volunteers
revealed no sex-related differences in the pharmacokinetic parameters
of bupropion.
CLINICAL TRIALS
The efficacy of ZYBAN as an aid to smoking cessation was demonstrated in
3 placebo-controlled, double-blind trials in nondepressed chronic cigarette smokers (n = 1,940,
≥15 cigarettes per day). In these studies, ZYBAN was used in conjunction with individual
smoking cessation counseling.
The first study was a dose-response trial conducted at 3 clinical centers. Patients in this study
were treated for 7 weeks with 1 of 3 doses of ZYBAN (100, 150, or 300 mg/day) or placebo;
quitting was defined as total abstinence during the last 4 weeks of treatment (weeks 4 through 7).
Abstinence was determined by patient daily diaries and verified by carbon monoxide levels in
expired air.
Results of this dose-response trial with ZYBAN demonstrated a dose-dependent increase in
the percentage of patients able to achieve 4-week abstinence (weeks 4 through 7). Treatment
with ZYBAN at both 150 and 300 mg/day was significantly more effective than placebo in this
study.
Table 1 presents quit rates over time in the multicenter trial by treatment group. The quit rates
are the proportions of all persons initially enrolled (i.e., intent to treat analysis) who abstained
from week 4 of the study through the specified week. Treatment with ZYBAN (150 or
300 mg/day) was more effective than placebo in helping patients achieve 4-week abstinence. In
addition, treatment with ZYBAN (7 weeks at 300 mg/day) was more effective than placebo in
helping patients maintain continuous abstinence through week 26 (6 months) of the study.
The second study was a comparative trial conducted at 4 clinical centers. Four treatments
were evaluated: ZYBAN 300 mg/day, nicotine transdermal system (NTS) 21 mg/day,
combination of ZYBAN 300 mg/day plus NTS 21 mg/day, and placebo. Patients were treated for 9 weeks.
Treatment with ZYBAN was initiated at 150 mg/day while the patient was still
smoking and was increased after 3 days to 300 mg/day given as 150 mg twice daily. NTS
21 mg/day was added to treatment with ZYBAN after approximately 1 week when the patient
reached the target quit date. During weeks 8 and 9 of the study, NTS was tapered to 14 and
7 mg/day, respectively. Quitting, defined as total abstinence during weeks 4 through 7, was
determined by patient daily diaries and verified by expired air carbon monoxide levels. In this
study, patients treated with any of the 3 treatments achieved greater 4-week abstinence rates than
patients treated with placebo.
Table 2 presents quit rates over time by treatment group for the comparative trial.
When patients in this study were followed out to one year, the superiority of ZYBAN and the
combination of ZYBAN and NTS over placebo in helping patients to achieve abstinence from
smoking was maintained. The continuous abstinence rate was 30% (95% CI 24-35) in the
ZYBAN treated patients, and 33% (95% CI 27-39) for patients treated with the combination at
26 weeks compared with 13% (95% CI 7-18) in the placebo group. At 52 weeks, the continuous
abstinence rate was 23% (95% CI 18-28) in the ZYBAN treated patients, and 28% (95% CI
23-34) for patients treated with the combination, compared with 8% (95% CI 3-12) in the
placebo group. Although the treatment combination of ZYBAN and NTS displayed the highest
rates of continuous abstinence throughout the study, the quit rates for the combination were not
significantly higher (p>0.05) than for ZYBAN alone.
The comparisons between ZYBAN, NTS, and combination treatment in this study have not
been replicated, and, therefore should not be interpreted as demonstrating the superiority of any
of the active treatment arms over any other.
The third study was a long-term maintenance trial conducted at 5 clinical centers. Patients in
this study received open-label ZYBAN 300 mg/day for 7 weeks. Patients who quit smoking while receiving
ZYBAN (n = 432) were then randomized to ZYBAN 300 mg/day or placebo for
a total study duration of 1 year. Abstinence from smoking was determined by patient self-report
and verified by expired air carbon monoxide levels. This trial demonstrated that at 6 months,
continuous abstinence rates were significantly higher for patients continuing to receive ZYBAN
than for those switched to placebo (p<0.05; 55% versus 44%).
Quit rates in clinical trials are influenced by the population selected. Quit rates in an
unselected population may be lower than the above rates. Quit rates for ZYBAN were similar in
patients with and without prior quit attempts using nicotine replacement therapy.
Treatment with ZYBAN reduced withdrawal symptoms compared to placebo. Reductions on
the following withdrawal symptoms were most pronounced: irritability, frustration, or anger;
anxiety; difficulty concentrating; restlessness; and depressed mood or negative affect. Depending
on the study and the measure used, treatment with ZYBAN showed evidence of reduction in
craving for cigarettes or urge to smoke compared to placebo.
Use In Patients With Chronic Obstructive Pulmonary Disease (COPD): ZYBAN was
evaluated in a randomized, double-blind, comparative study of 404 patients with mild-tomoderate
COPD, defined as FEV1≥35%, FEV1/FVC≤70% and a diagnosis of chronic bronchitis,
emphysema and/or small airways disease. Patients aged 36 to 76 years were randomized to
ZYBAN 300 mg/day (n = 204) or placebo (n = 200) and treated for 12 weeks. Treatment with
ZYBAN was initiated at 150 mg/day for 3 days while the patient was still smoking and increased
to 150 mg twice daily for the remaining treatment period. Abstinence from smoking was
determined by patient daily diaries and verified by carbon monoxide levels in expired air.
Quitters are defined as subjects who were abstinent during the last 4 weeks of treatment. Table
3 shows quit rates in the COPD Trial.
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