|
CLINICAL PHARMACOLOGY
Pharmacodynamics and Pharmacological Actions
Immediate Release Tablets: The neurochemical
mechanism of the antidepressant effect of bupropion is
not known. Bupropion does not inhibit monoamine oxidase.
Compared to classical tricyclic antidepressants, it is
a weak blocker of the neuronal uptake of serotonin and
norepinephrine; it also inhibits the neuronal re-uptake
of dopamine to some extent.
Bupropion produces dose-related central nervous system
(CNS) stimulant effects in animals, as evidenced by increased
locomotor activity, increased rates of responding in various
schedule-controlled operant behavior tasks, and, at high
doses, induction of mild stereotyped behavior.
Bupropion causes convulsions in rodents and dogs at doses
approximately tenfold the dose recommended as the human
antidepressant dose.
Sustained Release Tablets: Bupropion
is a relatively weak inhibitor of the neuronal uptake
of norepinephrine, serotonin, and dopamine, and does not
inhibit monoamine oxidase. The mechanism of action of
bupropion, as with other antidepressants, is unknown and
the mechanism by which bupropion enhances the ability
of patients to abstain from smoking is also unknown. However,
it is presumed that this action is also mediated by nonadrenergic
and/or dopaminergic mechanisms.
Pharmacokinetics
For the Immediate Release Tablet Only: Several
of the known metabolites of bupropion are pharmacologically
active, but their potency and toxicity relative to bupropion
have not been fully characterized. However, because of
their longer elimination half-lives, the plasma concentrations
of at least two of the known metabolites can be expected,
especially in chronic use, to be very much higher than
the plasma concentration of bupropion. This is of potential
clinical importance because factors or conditions altering
metabolic capactiy (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 these active metabolites.
Furthermore, bupropion has been shown to induce its own
metabolism in three animal species (mice, rats, and dogs)
following subchronic administration. If induction also
occurs in humans, the relative contribution of bupropion
and its metabolites to the clinical effects of bupropion
HCl may be changed in chronic use.
Plasma and urinary metabolites so far identified include
biotransformation products formed via reduction of the
carbonyl group and/or hydroxylation of the tert-butyl
group of bupropion. Four basic metabolites have been identified.
They are the erythro- and threo-amino alcohols of bupropion,
the erythro-amino diol of bupropion, and a morpholinol
metabolite (formed from hydroxylation of the tert-butyl
group of bupropion).
The morpholinol metabolite appears in the systemic circulation
almost as rapidly as the parent drug following a single
oral dose. Its peak level is three times the peak level
of the parent drug; it has a half-life on the order of
24 hours; and its AUC to 0 to 60 hours is about 15 times
that of bupropion.
The threo-amino alcohol metabolite has a plasma concentration-time
profile similar to that of the morpholinol metabolite.
The erythro-amino alcohol and the erythro-amino diol metabolites
generally cannot be detected in the systemic circulation
following a single oral dose of the parent drug. The morpholinol
and the threo-amino alcohol metabolites have been found
to be half as potent as bupropion in animal screening
tests for antidepressant drugs.
For the Sustained Release Tablet Only: 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
two-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
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. However, the fraction
of the oral dose of bupropion HCl excreted unchanged was
only 0.5%, a finding documenting the extensive metabolism
of bupropion.
The mean (±% CV) apparent clearance (CI/F) estimated
from two single-dose (150-mg) studies are 135 (±20%)
and 209 L/hr (±21%). Following chronic dosing of
150 mg of bupropion HCl sustained release tablets every
12 hours for 14 days (n=34), the mean CI/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.
Special Populations
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: For the Sustained Release Tablets Only: The disposition
of bupropion following a single 200-mg oral dose was compared
in eight healthy volunteers and eight weight- and age-matched
volunteers with alcoholic liver disease. The half-life
of the morpholinol metabolite (hydroxybupropion) was significantly
prolonged in subjects with alcoholic liver disease (32
hours [±41%] versus 21 hours [±23%]). The
differences in half-life for bupropion and the other metabolites
in the two patient groups were minimal. For the Immediate
Release Tablets Only: The effect of other diseases states
and altered organ function on the metabolism and/or elimination
of bupropion has not been studied in detail. However,
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 conjugation in the liver prior to urinary excretion.
The preliminary results of a comparative single-dose pharmacokinetic
study in normal versus cirrhotic patients indicated that
half-lives of the metabolites were prolonged by cirrhosis
and that the metabolites accumulated to levels two to
three times those in normals.
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 or an enlarged heart on x-ray),
there was substantial interpatient variability (twofold
to fivefold) in the trough steady-state concentrations
of bupropion and the morpholinol and threo-amino alcohol
metabolites. This variability was in the same range of
the variability observed in healthy volunteers (threefold
to eightfold). In addition, the steady-state plasma concentrations
of these metabolites were 10 to 100 times the steady-state
concentrations of the parent drug.
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.
Smokers: 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 bupropion, there was no statistically
significant difference in Cmax, half-life, tmax, AUC,
or clearance of bupropion or its active metabolites between
smokers and nonsmokers.
CLINICAL STUDIES
Anti-Depression
The efficacy of the immediate-release formulation
of bupropion as a treatment for depression was established
in two 4-week, placebo-controlled trials in adult inpatients
with depression and in one 6-week, placebo-controlled
trial in adult outpatients with depression. In the first
study, patients were titrated in a bupropion dose range
of 300 to 600 mg/day on a three times daily schedule;
78% of patients received maximum doses of 450 mg/day or
less. This trial demonstrated the effectiveness of the
immediate-release formulation of bupropion on the Hamilton
Depresssion Rating Scale (HDRS) total score, the depressed
mood item (item 1) from that scale, and the Clinical Global
Impressions (CGI) severity score. A second study included
two fixed doses of the immediate-release formulation of
bupropion (300 and 450 mg/day) and placebo. This trial
demonstrated the effectiveness of the immediate-release
formulation of bupropion, but only at 450-mg/day dose;
the results were positive for the HDRS total score and
the CGI severity score, but not for HDRS item 1. In the
third study, outpatients received 300 mg/day of the immediate-release
formulation of bupropion. This study demonstrated the
effectiveness of the immediate-release formulation of
bupropion on the HDRS total score, HDRS item 1, the Montgomery-Asberg
Depression Rating Scale, the CGI severity score, and the
CGI improvement score.
Although there are not as yet independent trials demonstrating
the antidepressant effectiveness of the sustained-release
formulation of bupropion, studies have demonstrated the
bioequivalence of the immediate-release and sustained-release
forms of bupropion under steady state conditions, i.e.,
bupropion sustained-release 150 mg twice daily was shown
to be bioequivalent to the 100 mg three times daily dose
of the immediate-release formulation of bupropion, with
regard to both rate and extent of absorption, for parent
drug and metabolites.
Smoking Cessation
The efficacy of bupropion HCl as an aid to smoking cessation
was demonstrated in two placebo-controlled, double-blind
trials in nondepressed chronic cigarette smokers (n=1508,
³15 cigarettes per day). In these studies, bupropion
was used in conjuction with individual smoking cessation
counseling.
The first study was a dose-response trial conducted at
three clinical centers. Patients in this study were treated
for 7 weeks with one of three doses of bupropion HCl (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 bupropion HCl
demonstrated a dose-dependent increase in the percentage
of patients able to achieve 4-week abstinence (weeks 4
through 7). Treatment with bupropion HCl 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 bupropion HCl (150
or 300 mg/day) was more effective than placebo in helping
patients achieve 4-week abstinence. In addition, treatment
with bupropion HCl (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.
| TABLE
1 Dose-Response Trial: Quit Rates by Treatment Group |
| Abstinence From Week 4 Through
Specified Week |
Placebo (n=151) % (95%
Cl) |
Bupropion HCl SR 100 mg/day
(n=153) %
(95% Cl) |
Bupropion HCl SR 150 mg/day
(n=153) %
(95% Cl) |
Bupropion HCl SR 300 mg/day
(n=156) %
(95% Cl) |
| Week
7 (4-week quit) |
17%
(11-23) |
22%
(15-28) |
27%*
(20-35) |
36%*
(28-43) |
| Week
12 |
14%
(8-19) |
20%
(13-26) |
20%
(14-27) |
25%*
(18-32) |
| Week
26 |
11%
(6-16) |
16%
(11-22) |
18%
(12-24) |
19%*
(13-25) |
| *
Significantly different from placebo (P£0.05). |
The second study was a comparative trial conducted at four
clinical centers. Four treatments were evaluated: bupropion
HCl sustained release tablets, 300 mg/day, nicotine transdermal
system (NTS) 21 mg/day, combination of bupropion HCl sustained
release tablets 300 mg/day plus NTS 21 mg/day, and placebo.
Patients were treated for 9 weeks. Treatment with bupropion
HCl sustained release tablets 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 bupropion HCl sustained
release tablets 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, patient treated with either bupropion HCl
sustained release tablets or NTS achieved greater 4-week
abstinence rates than patients treated with placebo. In
addition, patients treated with the combination of bupropion
HCl sustained release tablets and NTS achieved higher abstinence
rates than patients treated with either of the individual
active treatments alone, although only the comparison with
NTS achieved statistical significance.
TABLE 2 presents quit rates over time by treatment group
for the comparative trial. Both bupropion HCl sustained
release tablets and NTS were more effective than placebo
in helping patients maintain abstinence through week 10
of the study. The treatment combination of bupropion HCl
sustained release tablets and NTS displayed the highest
rates of continuous abstinence throughout the study.
| TABLE
2 Comparative Trial: Quit Rates by Treatment Group |
| Abstinence From Week 4 Through
Specified Week |
Placebo (n=160) % (95%
Cl) |
NicotineTransdermal System
(NTS) 21 mg/day (n=244) % (95% Cl) |
Bupropion HCl SR 300 mg/day
(n=244)%
(95% Cl) |
Bupropion
HCl SR 300 mg/day and NTS 21 mg/day (n=245) %
(95% Cl) |
| Week 7 (4-week
quit) |
23% (17-30) |
36%* (30-42) |
49%*†
(43-56) |
58%*†‡
(51-64) |
| Week 10 |
20% (14-26) |
32%* (26-37) |
46%*†
(39-52) |
51%*†
(45-58) |
| *
P£0.01 versus
placebo. |
| †
P£0.01 versus
NTS. |
| ‡
P=0.06 versus bupropion HCl. |
Quit rates in clinical trials
are influenced by the population selected. Quit rates in
an unselected population may be lower than the above rates.
Treatment with bupropion HCl sustained release tablets 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 bupropion
HCl sustained release tablets showed evidence of reduction
in craving for cigarettes or urge to smoke compared to placebo.
|
|
