Clinical Therapeutics/Volume 27, Number 11, 2005
Bupropion for Major Depressive Disorder:
Pharmacokinetic and Formulation Considerations
James W. Jefferson, MD1;James F. Pradko, MSc, MD2; and Keith T. Muir, PhD 3
1Madison Institute of Medicine and Department of Psychiatry, University of Wisconsin Medical School,
Madison, Wisconsin; 2Bay Pointe Medical Center, New Baltimore, Michigan, and Mount Clemens General
Hospital and St. John Hospital, Detroit, Michigan; and 3Division of Clinical Pharmacology, GlaxoSmithKline,
Research Triangle Park, North Carolina
ABSTRACT
Background: Major depressive disorder (MDD) is
a common psychiatric condition, with 6.6% of the
adult population in the United States experiencing a
major depressive episode during any given year. De-
pressed patients must receive adequate treatment to
maximize the likelihood of clinical success. Bupropion
hydrochloride, a noradrenergic/dopaminergic antide-
pressant, is available in 3 oral formulations: immediate
release (IR) (given TID), sustained release (SR) (given
BID), and extended release (XL) (given QD). Under-
standing the pharmacokinetic (PK) properties and for-
mulations of bupropion can help optimize clinical use.
Objectives: The aims of this article were to provide
a review of the PK properties of bupropion and identi-
fy its various formulations and clinical applications to
help optimize treatment of MDD.
Methods: In this review, data concerning PK trials/
reports were collected from articles identified using a
PubMed search. The search was conducted without
date limitations and using the search terms bupropion,
bupropion SR, bupropion XL, bupropion pharmaco-
kinetics, bupropion metabolism, and bupropion drug
interactions. Additional reports were selected from
references that appeared in articles identified in the
original search. In addition, data from studies summa-
rized in product information and labeling were ob-
tained. All available information, concentrating on
studies in humans, pertinent to bupropion PK proper-
ties and/or formulations was included.
Results: Bupropion is extensively metabolized by
the liver (tl/2, -21 hours). Hydroxybupropion, the pri-
mary active metabolite (tl/2, -20 hours), is formed by
cytochrome P450 (CYP) 2B6. At steady state, Cmax of
hydroxybupropion is 4- to 7-fold higher, and the AUC
is -10-fold greater, compared with those of the parent
drug. Threohydrobupropion and erythrohydrobupro-
November 2005
pion (mean [SD] tl/2 values, -37 [13] and -33 [10] hours,
respectively), the other active metabolites of bupro-
pion, are formed via nonmicrosomal pathways. Rela-
tive to bupropion, the Cmax values are -5-fold greater
for threohydrobupropion and similar for erythrohy-
drobupropion. Based on a mouse antitetrabenazine
model, hydroxybupropion is -50% as active as bu-
propion, and threohydrobupropion and erythrohy-
drobupropion are -20% as active as bupropion. Bu-
propion lowers the seizure threshold and, therefore,
concurrent administration with other agents that
lower the seizure threshold should be undertaken cau-
tiously. Potential interactions with other agents that
are metabolized by CYP2B6 should be considered. In
addition, bupropion inhibits CYP2D6 and may re-
duce clearance of agents metabolized by this enzyme.
Absorption of the XL formulation is prolonged com-
pared with the IR and SR formulations (T.... -5 hours vs
-1.5 and -3 hours, respectively). Bupropion is dosed
without regard to food.
Conclusions: Understanding the PK profile and for-
mulations of bupropion can help optimize clinical use.
Bupropion is metabolized extensively, resulting in 3
active metabolites. This metabolic profile, various pa-
tient factors (eg, age, medical illnesses), and poten-
tial drug interactions should be considered when pre-
scribing bupropion. The 3 formulations--bupropion,
bupropion SR, and bupropion XL--are bioequivalent
and offer options to optimize treatment for patients
with MDD. (Clin Ther. 2005;27:1685-1695) Copy-
right © 2005 Excerpta Medica, Inc.
Acceptedfor publication September6, 2005.
doi:l 0.1015/j.clinthera.2005.11.011
0149-2918/05/$19.00
Printed in the USA. Reproduction in whole or part is not permitted.
Copyright © 2005 Excerpta Medica, Inc.
1685
 Clinical Therapeutics
Key words: bupropion, depression, major depres-
sive disorder, pharmacokinetics, formulations, drug
interactions.
INTRODUCTION
Major depressive disorder (MDD) is a common psy-
chiatric disorder, with 6.6% of the adult population
in the United States experiencing a major depressive
episode during any given year. 1 Depressive episodes
are often chronic and are recurrent in at least 60%
of patients. 2 Not all patients respond to initial treat-
ment with an antidepressant, with response rates in
clinical trials ranging from 50% to 75%. 3 It is impor-
tant that depressed patients receive adequate antide-
pressant treatment to maximize the likelihood of clini-
cal success.
The purposes of this review were to summarize the
available data concerning the pharmacokinetic (PK) prop-
erties and formulations of bupropion hydrochloride
(HC1), and to present the clinical applicability to allow cli-
nicians to further optimize the use of this antidepressant.
MATERIALS AND METHODS
In this review, PK trials/reports were identified using a
PubMed search. The search was conducted without
date limitations and using the search terms bupropi-
on, bupropion SR, bupropion XL, bupropion phar-
macokinetics, bupropion metabolism, and bupropion
drug interactions. Additional reports were selected
from references in the original search. Because the
amount of data obtained from the literature was lim-
ited, especially regarding formulations, data from
studies summarized in product information and label-
ing were obtained. All information pertinent to the PK
properties and formulations of bupropion, concen-
trating on data in humans, was identified.
Background
Bupropion, a norepinephrine/dopamine reuptake
inhibitor (NDRI), has been available in the United
States for the treatment of MDD since 1989. 4-7 First
marketed as an immediate-release (IR) formulation, it
was recommended for TID administration. However,
because of the inconvenience of multiple daily dosing
and Cmax-related adverse events (AEs) (eg, insomnia,
seizure), a BID sustained-release (SR) formulation was
introduced in the United States in 1996.8,9 However,
compliance with the BID regimen remained problem-
1686
atic, 1°,11 promulgating the development of extended-
release (XL) bupropion, a QD formulation, which
was approved in 2003 by the US Food and Drug
Administration (FDA) for the treatment of MDD in
adults.7,12
Bupropion inhibits the neuronal reuptake of norepi-
nephrine and dopamine. 4 It has no appreciable affin-
ity for postsynaptic receptors, including receptors of
histamine, et- or ]3-adrenergics, serotonin, ace@choline,
or dopamine. 4 Of clinical importance, the mechanism
of action of bupropion lacks any significant serotoner-
gic component, which may account for its low risk
for sexual AEs, which is 4- to 6-fold greater with se-
lective serotonin reuptake inhibitors (SSRIs) and ven-
lafaxine XL in patients not predisposed to sexual
dysfunction. 4,13 The antidepressant efficacy of bupro-
pion has been demonstrated in comparisons with
placebo in 4-, 6-, and 8-week 14-16 studies and in a
long-term relapse-prevention study. 17 Similar clinical
efficacy has been found relative to SSRIs, tricyclic
antidepressants, and trazodone. 12,15,18-2° Indeed, the
American Psychiatric Association Practice Guideline 3
recognizes bupropion as an effective antidepressant
and notes that all antidepressants have generally com-
parable efficacy. As with other antidepressants, sever-
al weeks may be required for antidepressant effects to
develop. 3
The tolerability profile of bupropion is well docu-
mented, with thousands of patients participating in
clinical trials and >40 million clinical-use exposures
for all uses. 12 The most common (incidence, >10%)
AEs associated with the use of bupropion have been
found to be headache (27% vs 23% for placebo), dry
mouth (16% vs 7%; P < 0.05), nausea (13% vs 8%;
P < 0.05), and insomnia (11% vs 7%; P < 0.05). 21
Bupropion is associated with a dose-related risk for
seizure (0.1% at doses up to 300 mg/d with the SR
formulation and 0.4% at doses up to 450 mg/d with
the IR formulation). 8 Based on the literature search,
no formal studies assessing possible seizure risk asso-
ciated with the use of the XL formulation have been
conducted. To minimize risk for seizure, patients should
be screened for predisposing factors, clinical situa-
tions, and concomitant medications that may decrease
seizure threshold. Because of the NDRI mechanism of
action, lack of affinity for histamine receptors, and
lack of serotonergic activity, bupropion has a number
of attributes that are important for long-term therapy.
Specifically, bupropion has been associated with low
Volume 27 Number 11

incidences of sedation (2%-3% vs 2% with placebo),
weight gain (2%-3% vs 4% with placebo), and sexu-
al dysfunction (risk, 4- to 6-fold less compared with
SSRIs and venlafaxine XL). 5-7,12,13
Bupropion has been studied for a number of other
uses, including treatment of bipolar disorder and
attention-deficit hyperactivity disorder (ADHD), and
as an aid to smoking cessation or weight lOSS.22-25 Of
these, only use as an aid to smoking cessation is an
FDA-approved indication, and this use is limited to
the SR formulation. The present analysis, however, fo-
cuses on PK data and attributes of the 3 formulations
of bupropion with the aim of optimizing the treatment
of MDD in adults.
Pharmacokinetic Properties
Absorption and Distribution
Bupropion is rapidly absorbed in the gastrointes-
tinal tract after oral administration of the IR tablet,
with Tmax values of 1.3 to 1.9 hours (mean, -1.5 hours). 26
Absorption of bupropion has been found to be nearly
100%.27 However, systemic bioavailability of the par-
ent drug has been found to be <100% due to first-pass
metabolism. 27 By design, the absorption of bupropion
is prolonged with the SR and XL formulations, with
Tmax values of -3 and -5 hours, respectively. Cmax and
AUC values increase proportionally with dose for the
IR, 26 SR, 28 and XL 29 formulations. Food does not ap-
pear to impair absorption. 5-7
Bupropion is extensively distributed throughout
the body, as evidenced by a mean Vd at steady state
of 19 L/kg. 26 Bupropion binding to human plasma
protein is 82% to 88%, a range not considered to rep-
resent high levels of protein binding. 26 Thus, protein-
binding interactions with bupropion are not likely to
be of clinical importance.
Positron emission tomography (PET) imaging
studies in 6 healthy volunteers found that bupropion
and its metabolites, at steady state after adminis-
tration of recommended doses of bupropion SR, par-
tially (-25%) occupied brain striatal dopamine trans-
porter for at least 24 hours after discontinuation of
treatment. 3° After the administration of recommend-
ed doses of bupropion in a PET study31 involving
8 depressed patients and in a single photon emission
computed tomography study 32 involving 7 de-
pressed patients, dopamine transporter occupancy was
found to be comparable to that observed in healthy
volunteers.
November 2005
J.W. Jefferson et al.
Metabolism and Elimination
Bupropion is extensively metabolized in the liver
after oral administration. 5-7,27 Cmax values of hydroxy-
bupropion (OH-BUP), the primary active metabolite
of bupropion, are 4- to 7-fold those of bupropion,
whereas total exposure to OH-BUP (based on AUC) is
-10-fold that of the parent drug. In vivo studies using
the mouse antitetrabenazine model of depression have
found OH-BUP to be half as potent as bupropion. The
concentration of threohydrobupropion, another ac-
tive metabolite of bupropion, in human plasma has
been found to be -5-fold that of bupropion. The con-
centration of erythrohydrobupropion, the third active
metabolite, has been found to be similar to that of
bupropion. However, both threohydrobupropion and
erythrohydrobupropion have been associated with
just 20% of the antidepressant activity of parent drug
in this animal model. 5-7,27
In vitro studies 33,34 with human hepatic microsomes
have shown that the primary cytochrome P450 (CYP)
enzyme in the metabolism of bupropion to OH-BUP
is CYP2B6. The CYP1A2, 2A6, 2C9, 2D6, 2E1, and
3A4 isoforms also play a role in the metabolism of the
drug, but to a lesser extent. 33-35 Other metabolic path-
ways include the formation of threohydrobupropion
and erythrohydrobupropion by carbonyl reductase, a
nonmicrosomal enzyme in the liver and gut. 36 In vitro 33
and in vivo 37 studies have shown that bupropion in-
hibits CYP2D6 activity. Thus, a potential for interac-
tions with drugs metabolized by CYP2D6 exists and is
described subsequently.
The mean (SD) elimination h/2 of bupropion is
-21 (9) hours, and that of OH-BUP is similar (-20
[5] hours). 5-7 The tl/2 values of erythrohydrobupropion
and threohydrobupropion are longer (-33 [10] and 37
[13] hours, respectively).5-7 Therefore, -7 to 10 days
are required for bupropion and its metabolites to
reach steady state. Bupropion and its metabolites ex-
hibit linear PK properties with long-term administra-
tion of 300 to 450 mg/d. 5-7 Approximately 0.5% of bu-
propion is excreted in the urine as unchanged drug. 26
PHARMACOGENOMIC PROPERTIES
A study of the PK properties of bupropion and OH-BUP
was conducted in 121 healthy male volunteers who
underwent genotyping for polymorphisms of CYP2B6
expression. 34 Subjects received a single 150-rag dose
of bupropion IR. That study found large interindivid-
ual variability in the PK properties of bupropion and
1 687
 Clinical Therapeutics
OH-BUP, with a 10-fold range observed in most of the
PK parameters. However, the investigators concluded
that none of the CYP2B6 alleles had a major effect
on the PK properties of bupropion, although the
CYP2B6* allele was associated with a 1.66-fold in-
crease in bupropion clearance compared with other
alleles assessed, resulting in significantly higher Cmax
(40%--50%; P = 0.03) and AUC (20%-40%; P <
0.01) of OH-BUP. Because bupropion and OH-BUP
are both pharmacologically active, the significance of
these findings is unclear.
Drug-Drug Interactions
Because bupropion lowers the seizure threshold, it
should be used cautiously with other medications that
also lower seizure threshold, s including other anti-
depressants, antipsychotics, tramadol, and theoph-
ylline. 3s,39 In addition, care should be used when al-
cohol or medications such as benzodiazepines are
discontinued abruptly due to increased risk for seizure
during withdrawal states, s Because bupropion in-
creases dopaminergic activity, the potential exists for
interactions with other dopaminergic agents (eg, levo-
dopa). 4° As with other antidepressants, bupropion
should not be administered concurrently with, or
within 14 days after discontinuation of, a monoamine
oxidase inhibitor, to allow time for monoamine oxi-
dase activity to recover.5-7
Potential PK interactions between bupropion and
other drugs are summarized in Table I. Because a
major pathway in the metabolism of bupropion to
OH-BUP is CYP2B6, there is a potential for other drugs
metabolized by this enzyme to cause competitive inhi-
bition of metabolism. 33 Table I lists drugs other than
bupropion that are metabolized by CYP2B6. How-
ever, the literature search failed to identify studies
showing clinical interactions between bupropion and
other CYP2B6 substrates. The likely explanation is
that bupropion is metabolized by other pathways in
addition to CYP2B6.
As mentioned previously, bupropion inhibits the
activity of CYP2D6, an important enzyme that dis-
plays genetic polymorphism and metabolizes several
therapeutic classes of drugs, including antidepressants,
[g-blockers, and antiarrhythmic agents. 46 Based on the
literature search, studies of the effects of bupropion
on CYP2D6 activity are limited. In an open-label
study, <37 the effects of concurrent steady-state admin-
istration of bupropion SR 150 mg BID and a single
1688
50-mg dose of desipramine, the primary route of me-
tabolism of which is CYP2D6, in 15 CYP2D6-extensive
metabolizers was examined. Desipramine clearance
was decreased, with resultant 2-, 5-, and 2-fold higher
C. . . . AUC, and tl/2 values, respectively. Also, an open-
label study47 of adjuvant therapy with bupropion SR
for 8 weeks with venlafaxine, paroxetine, or fluoxetine
(minimum of 6 weeks of prior treatment) in 18 de-
pressed patients found inhibition of venlafaxine me-
tabolism, resulting in a significant, -2.5-fold higher
plasma venlafaxine concentration at steady state (Css)
(P < 0.01), but no effect on paroxetine or fluoxetine Cs~.
Last, in a repeated-measures, placebo-controlled study,51
the mean (SD) dextromethorphan/dextrophan ratio
was significantly increased (0.012 [0.012] vs 0.418
[0.302]; P < 0.001), when bupropion SR 150 mg BID
was administered for 17 days to 21 smokers given a
single 30-mg oral dose of dextromethorphan at base-
line and at the end of bupropion treatment, indicating
inhibition of CYP2D6 activity.
The PK properties of bupropion might also be al-
tered by compounds known to induce various meta-
bolic pathways of bupropion. For example, in a
placebo-controlled study43 in 12 patients with mood
disorders given a single 150-mg dose of bupropion,
bupropion Cmax and AUC were significantly decreased
(by 87% and 91%, respectively; both, P < 0.001) with
concurrent administration of carbamazepine (mean
[SD] dose, 942 [254] mg/d), which induces CYP2B6,
3A4, and 1A2 activity.52 However, OH-BUP Cmax and
AUC were simultaneously increased (by 71% and
50%, respectively; P < 0.007 and P < 0.05). Again, be-
cause both bupropion and OH-BUP are pharmacolog-
ically active, the investigators considered the signifi-
cance of these findings difficult to quantify.
Pharmacokinetic Properties in Special Populations
Several clinical studies have assessed the effects of
age, sex, smoking status, and organ dysfunction on
the PK properties of bupropion and its metabolites.
Effects of Age
Elderly Patients
The influence of advanced age on the disposition of
bupropion after single and multiple doses has been ex-
amined. In an open-label study 53 in 6 depressed pa-
tients aged 63 to 76 years, a single oral 75- to 100-mg
dose of bupropion IR was administered. The mean tl/2
values for bupropion (34.2 hours) and its metabolites
Volume 27 Number 11
 J.W. Jefferson et al,

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November 2005 1689

 Clinical Therapeutics
(34.2, 38.8, and 61.4 hours for OH-BUP, threohy-
drobupropion, and erythrohydrobupropion, respec-
tively) seemed longer compared with those previous-
ly reported in younger subjects. 54,55 The small sample
size and lack of a comparative younger group made
definitive conclusions difficult. In a controlled study 56
in 23 healthy volunteers aged <40 years (n = 12) or
>65 years (n = 11) administered a bupropion IR 150-mg
dose, bupropion mean (SD) Cma x w a s higher in the
older patients compared with their younger counter-
parts (0.62 [0.23] tlmol/L vs 0.44 [0.12] tlmol/L; P =
0.032), but bupropion and OH-BUP mean (SD) AUG
values were similar between the 2 groups (bupropion,
3.18 [0.75] t~mol/L • h vs 3.28 [0.86] t~mol/L • h; OH-
BUP, 68.75 [29.31] tlmol/L • h vs 55.43 [28.96] tlmol/
L .h).
Adolescent Patients
Stewart et a157 reported the findings from a single-
dose study in 75 healthy adolescents (age, 13-
18 years) of both sexes, half of whom were smokers.
Subjects were administered one 150-mg tablet of
bupropion SR. The effect of age on the PK properties
of bupropion and OH-BUP was assessed by compar-
ing the PK parameters in adolescent nonsmokers
with those in smoking and nonsmoking adults from
an earlier study. 58 PK parameters of the parent com-
pound and aminoalcohol metabolites were not com-
pared statistically but did not differ dramatically
between the adolescents and adults. However, Cmax
and AUC of OH-BUP were lower in the adolescents.
Dose-normalized C ..... and AUC of OH-BUP were
-2- to 3-fold higher in the adults. In an open-label
study by Daviss et al, 28 the steady-state PK properties
of bupropion were examined in 19 adolescent (age,
11-18 years) patients with ADHD or depressive dis-
orders who received bupropion SR 100 or 200 mg/d
for 2 weeks. In contrast to the study by Stewart et
a l l 7 this study in adolescents found that the mean
h/2 values of bupropion (12.1 hours; P < 0.001) and
threohydrobupropion (26.3 hours; P < 0.05) were
significantly shorter, and AUC ratios of bupropion
metabolites were 19% to 80% higher (P _< 0.003),
compared with those previously reported in
adults. 5-7,58 These results suggest that developmental
factors may be important in the PK properties of bu-
propion in adolescent patients because of potentially
more rapid conversion of the drug to its active
metabolites.
1690
Effects of Gender
One of the first studies of the PK properties of
bupropion 26 assessed the effects of gender in 24 healthy
subjects who received bupropion 50-, 100-, and
200-mg single doses in a randomized, crossover
fashion. That study found that the drug exposure,
based o n Cma x (mean [SEM], 158 [11] ng/mL vs 125
[8] ng/mL; P < 0.05) and AUG (mean [SEM], 806
[59] ng/mL • h vs 621 [41] ng/mL • h; P < 0.05), was
higher in females. No significant differences were ob-
served in the body-weight-normalized parameters.
Hsyu et a158 examined the effects of gender in an
open-label study in 34 male and female healthy volun-
teers (17 smokers and 17 nonsmokers), the primary
objective of which was to determine the effects of smok-
ing on the PK properties of bupropion and its metabo-
lites. Patients received a single 150-mg dose of bupro-
pion. Statistical analysis showed no gender differ-
ences, with the exception of a clinically nonsignificant,
shorter mean (SD) tl/2 in males (17 [3] vs 20 [5] hours;
P = 0.02). However, the study by Stewart et a l l 7
which examined the effects of smoking in adolescent
subjects, found significantly higher exposures in fe-
males than in males (mean [SD] G. . . . 129 [5] ng/mL vs
102 [5] ng/mL [P < 0.05]; mean [SD] AUG, 1443
[67] ng/mL • h vs 1134 [55] ng/mL • h [P < 0.05]); the
investigators attributed these differences to differences
in weight between females and males. In the study by
Daviss et al, 28 no significant differences in PK param-
eters were observed between males and females.
Effects of Smoking,
Two clinical studies have been conducted to deter-
mine the impact of smoking on the PK properties of
bupropion and its metabolites (Hsyu et a158 and Stewart
et a157). Hsyu et a158 found no significant differences
in the PK properties of bupropion and OH-BUP in
smokers compared with nonsmokers. Similarly, Stewart
et a157 found no effect of smoking on the PK proper-
ties of bupropion in adolescents who smoked com-
pared with those who did not.
Hepatic Impairment
The effects of hepatic impairment on the PK prop-
erties of bupropion have been assessed in 8 patients
with alcoholic hepatic disease of unspecified severity 59
and in 17 patients with mild to severe hepatic cirrho-
sis. 6° In an open-label study, 59 the mean tl/2 of OH-BUP
was significantly longer in 8 patients with alcoholic
Volume 27 Number 11

hepatic disease compared with that in 8 healthy vol-
unteers (32.2 vs 21.1 hours; P < 0.05). The AUCs of
bupropion and OH-BUP were more variable in the
patients with alcoholic hepatic disease but were statis-
tically similar compared with those in the healthy sub-
jects. A separate, open-label study 6° found no statis-
tically significant differences in the PK properties of
bupropion or its active metabolites between 9 patients
with mild to moderate hepatic cirrhosis and 8 healthy
volunteers. However, in 8 patients with severe hepatic
cirrhosis, the bupropion Cmax and AUC values were
substantially increased (mean differences, -70% and
3-fold, respectively; P = 0.011 and P < 0.001) and
showed more interpatient variability compared with
values in healthy subjects. The mean bupropion tl/2
was statistically similar in patients with severe he-
patic cirrhosis compared with that in healthy subjects
(29 vs 19 hours). The OH-BUP C . . . . however, was
-69% lower (P < 0.001) in these cirrhotic patients.
Based on these data, it is recommended in the product
information that bupropion be used with caution and
at a reduced frequency of administration and/or dose
reduction be considered in patients with mild to mod-
erate hepatic impairment, and that bupropion be used
with extreme caution in patients with severe hepatic
cirrhosis, and that the dose not exceed 150 mg every
other day in patients with severe cirrhosis. 5-7
Renal Impairment
In an open-label study investigating the PK proper-
ties of bupropion SR in 8 smokers with end-stage re-
nal disease (ESRD), 61 bupropion, OH-BUP, and threo-
hydrobupropion concentrations were measured after
a single-dose administration of 150 mg. The bioana-
lyrical methodology used did not distinguish between
threohydrobupropion and erythrohydrobupropion; how-
ever, as mentioned previously, concentrations of eryth-
rohydrobupropion after single-dose administration of
150 mg are low. The Cmax (144 vs 126 ng/mL) and
AUC (1165 vs 1446 ng/mL • h) of bupropion were not
greatly different from those in historical controls. 5s,61
However, the AUCs of OH-BUP and threohydroxy-
bupropion were 2-fold (37,530 vs 15,883 ng/mL • h)
and 3-fold (17,136 vs 6190 vs ng/mL • h) greater, re-
spectively, compared with the values in the historical
controls. 5s,61 These findings suggest that Css of OH-BUP
and threohydrobupropion in patients with ESRD could
be 2-fold and 3-fold greater compared with those
in patients with normal renal function. Hemodialysis
November 2005
J.W. Jefferson et al.
produced decreases in bupropion, OH-BUP and threo-
hydrobupropion concentrations of -13%, -4%, and
-17%, respectively, over the 4-hour dialysis period. 61
Treatment of patients with renal impairment should be
initiated at a reduced dose, because bupropion metab-
olites might accumulate in such patients to a greater
extent than in patients with normal renal function.
Other Factors
No bupropion PK studies assessing the effects of
race, pregnancy, or obesity were identified in the liter-
ature search.
Formulations
Table II summarizes the primary characteristics of
the 3 available bupropion formulations. These formu-
lations were developed sequentially to better fulfill
clinical needs (ie, patients' concerns about convenience/
compliance related to multiple daily dosing, and toler-
ability related to Cmax). 8,10 Although convenience of
administration may have improved with the SR for-
mulation, 11 patients continued to have difficulty com-
plying with the BID dosing regimen. A syndicated
consumer quantitative research study 1° documented
that patients had difficulty using bupropion SR BID
compared with QD SSRIs and venlafaxine XL. In ad-
dition, patients receiving the SR formulation need to
follow specific administration instructions applicable
to the second dose (ie, the second dose should be ad-
ministered at least 8 hours after the first dose, but not
too close to bedtime so as to minimize insomnia). 5-7
By allowing for QD administration of up to 450 mg
in the morning, bupropion XL not only addresses the
issue of multiple daily dosing but also avoids high
plasma drug concentrations at bedtime, as seen with
the IR and SR formulations (Figure). 62,63
Bupropion IR is a conventional tablet formulation
designed to dissolve in gastric medium, allowing for
rapid release of the drug substance. 5 Bupropion SR
tablets were designed to prolong dissolution and hence
absorption by incorporating drug substance in a
methylcellulose matrix. 6 Bupropion XL is also a tablet
formulation designed to prolong absorption and
consists of a core of bupropion HC1 surrounded
by controlled-release and moisture-barrier coatings. 7
Because of the formulation characteristics of bupropi-
on SR and XL, neither formulation should be cut,
chewed, or crushed, which could lead to faster release
of bupropion.¢7 This precaution is particularly im-
1691
 Clinical Therapeutics

Table II. Prescribing information for the immediate-release (IR), sustained-release (SR), and extended-release
(XL) formulations of bupropion, s-7

IR SR XL

Dosing TID BID QD

Maximum dose per day, range, mg/d 300 4S0 300 400 300 4S0
Maximum single dose, mg 1 SO 200 4S0
Available strengths, mg 7S and 100 100, 1S0, and 200 1S0 and 300
Tm~×, h 1 2 3 S
Food effect None None None
Dosing instructions For )atients Equally divided doses Doses should be AM Doses should be AM,
TID, preferably and PM, ->8 hours 24 hours apart; do
_>6 h apart apart; avoid bedtime not cut, chew, or crush
dosing; do not cut,
chew, or crush

IR (100 mgTID)
SR (150 mg BID)
- - XL (300 mgQD)
I SO-
t~, j ,
E

L)
100
O
D_ f
, ]l I
t
- ".
', "-.
'
i
,' ,"~..
, .~
; ",
ii %
",x
£
D_
OD
50
¢U
E
¢tl
¢U

0 I I I I
0 6 12 18 24
Time After Study Drug Administration (h)

Figure. Plasma steady-state concentrations (Css) of the immediate-release (IR), sustained-release (SR), and extended-
release (XL) formulations of bupropion. (Data from Studies 254362 and 2S72, 6a GlaxoSmithKline, Research
Triangle Park, North Carolina, using the same liquid chromatography/mass spectrometry/mass spectrometry
assay procedure.)

portant with the XL formulation, in which a single
dose of 300 mg or more is used. 7 Generic formula-
tions of bupropion IR and SR are available in the
United States.
Bupropion SR 64 and XL 62 have been found to be bio-
equivalent to the IR formulation and to each other53
Bioequivalence criteria included demonstration of
equivalent delivery of the drug via the respective for-
mulations as measured by AUC, Cn~, and Cmin w h e n
multiple doses were administered until steady state
was achieved. Values for AUC, Cn~, and C~n in corn-
parisons of the 3 formulations are presented in Table III.
These outcome measures were applied to the bupropi-
on molecule and its 3 metabolites, and bioequivalence
was found in comparisons of the XL or SR formula-
tion with the IR formulation and of bupropion SR

1692 Volume 27 Number 11

 J.W. Jefferson et al.

Table III. Pharmacokinetic properties o f the immediate-release (IR), sustained-release (SR), and extended-release
(XL) formulations o f bupropion in the steady state. ~

Dosing AUC0_24, Geometric Cmax, Geometric Cmin, Geometric

Formulation/Comparison Regimen Mean, ng/mL • h Mean, ng/mL Mean, ng/mL

IR
Versus SR (Study 20664) 100 mg TID 1 744 1 60 27
Versus XL (Study 254362) 100 mg TI D 1 731 1 68 32
SR
Versus IR (Study 20664) 150 mg BID 1718 136 29
Versus XL (Study 257263) 150 mg BID 1562 136 25
XL
Versus IR (Study 2543 ~2) 300 mg QD 1545 161 26
Versus SR (Study 2572 ~3) 300 mg QD 1412 144 23

~Studies 206, 64 2543, 62 and 25726~ were open label, multidose, 2 way, crossover, steady state bioavailability comparisons+
Study 206 enrolled healthy male volunteers, whereas 2543 and 2572 enrolled healthy male and female volunteers. Compari
sons ofAUC, Crrax , and Crr, in with in each study met criteria for bioequ ivalence (90% CI of the ratio of means fell between 80% and
125% for the IR/SR comparison in Study 206, the IR/XLcomparison in Study 2543, and the SR/XL comparison in Study 2572).

w k h XL. However, based on a search of the lkerature,
no direct comparisons of efficacy between the 3 for-
mulations have been conducted.
In plasma, bupropion, in comrast with its metabo-
lites, has an initial rapid-distribution phase followed
by a slower terminal disposition (biphasic disposi-
t i o n ) Y This profile results in greater fluctuation
in plasma bupropion concemrations compared with
those of its metabolites, s,6s Tn~ x of bupropion has
been found to be -1.5, -3, and - 5 hours for bupropi-
on IR, SR, and XL, respectively. ~7 The 24-hour mean
plasma concentration-versus-time plots for bupropi-
on on administration of a 300-mg total daily dose of
each formulation until steady state are presented in
the figure. 62,63 The plasma concentration-versus-time
profiles for 450-my daily doses of bupropion IR (150 mg
TID) and XL (450 mg QD [morning]) are similar to
those of the 300-rag daily dose (Figure), but are pro-
po rtionally (5 0 %) higher.
The initial daily dose is 100 mg BID for the IR for-
mulation and 150 mg QD for the SR and XL formula-
tions. ~7 The dose is increased as early as day 4 of treat-
ment to the target antidepressant dose of 300 r~g/d, s 7
Once the target dose is reached, further dose increases
should not generally be made before the 7 to 10 days
required to reach steady state. ~7 Clinically, up to
4 weeks are typically required before the full antide-
pressant effect is seen. ~7 The maximum dose recom-
mended in the product labeling for the SR formulation
is 400 mg/d (200 mg BID), 6 compared with 450 mg/d
for both the IR s (150 mg TID) and XL 7 formulations
(450 mg QD [morning]). Patients being converted
from one formulation to another should be given the
same daily dose they are currently receiving, sT If this
is not possible, clinical judgment should be used in de-
termining whether the next highest or next lowest
dose should be given (eg, bupropion SR 400 mg/d
may be converted to 300 or 450 mg of bupropion XL
given QD). s 7 Different dosage strengths of the IR, s4
SR, 66 and XL 29 formulations are dose proportional,
meaning that within each formulation, tablet strengths
can be combined as needed (eg, 2 b u p r o p i o n XL
150-mg tablets provide the same dose and delivery as
a single 300-my tablet of bupropion XL). A dose of
450 mg of bupropion XL can be achieved by the ad-
ministration of three 150-mg tablets QD (morning) or
one 300-rag tablet together with one 150-rag tablet
QD (morning). s-7
CONCLUSIONS
Understanding the PK properties and formulations of
bupropion can help optimize clinical use. Bupropion
is metabolized extensively, resulting in 3 active metabo-
lites. This metabolic profile, various patient factors
(eg, age, medical illnesses), and potential drug interac-
tions should be considered when prescribing bupropi-

N o v e m b e r 2005 1693
 Clinical Therapeutics
on. The 3 formulations--bupropion, bupropion SR,
and bupropion XL--are bioequivalent and offer
options to optimize treatment for patients with
MDD.
ACKNOWLEDGM ENT
The authors acknowledge the support of J. Andrew
Johnston, PharmD, Innovaa Research, Chapel Hill,
North Carolina, for his help in preparing this review.
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