NDA
21-515
WELLBUTRIN
XL
|
Inhibitor |
Cmax (ng/ml) |
Molecular Weight |
IC50 (µM) |
IC50 (ng/ml) |
Cmax/IC50 |
|
Nelfinavira (free
base) |
[blacked out] |
567.79 |
2.5 |
1419 |
2.82 |
|
Ritonavir |
[blacked out] |
720.95 |
2.2 |
1586 |
2.33 |
|
Efavirenz |
[blacked out] |
315.68 |
5.5 |
|
2.35 |
|
Nefazodone |
[blacked out] |
506.5 |
25.4 |
12865 |
.025 |
|
Sertraline |
|
342.7 |
3.2 |
1097 |
0.17 |
|
Paroxetine |
[blacked out] |
374.8 |
1.6 |
600 |
0.10 |
|
Norfluoxetine |
[blacked out] |
331.8 |
4.2 |
1394 |
0.19 |
|
Fluvoxamine |
[blacked out] |
318.353 |
6.1 |
1942 |
0.28 |
aUsing the molecular weight
for the mesylate salt [blacked out] the Cmax/IC50 is 2.41
bConcentration expressed as
µM
The nature of this inhibition has not been determined. If it is competitive (and using a substrate concentration in vitro that was somewhat less than the Km for hydroxylation as in the published in vitro studies1,2), the IC50 would be 1-2 times greater than that of the Ki value, resulting in Cmax/Ki values even greater that interactions would likely occur if the Cmax/Ki is greater than 1, and possible if the Cmax/Ki is between 0.1 and 1, these in vitro studies suggest that potential for a CYP2B6-mediated drug interaction.6
In summary, there is in vitro evidence to show that bupropion hydroxylation is mediated by CYP2B6 and can be inhibited by ritonavir, efavirenz, nelfinavir, as well as by sertraline, paroxetine, norfluoxetine, and fluvoxamine. No clinical studies have been performed to evaluate this finding, and therefore the clinical relevance is unknown.
·
Is there data in the literature to rule out clinically significant drug
interactions between bupropion and
either SSRIs or protease inhibitors?
The
Sponsor has conducted a literature search evaluating concomitant use of
bupropion and various SSRIs and has found that these combinations are
reportedly well tolerated, with adverse events similar to those associated with
each monotherapy. These studies were
not designed to evaluate drug interaction effects on bupropion exposure. The Sponsor cites 3 reports in the
literature describing adverse events during combination therapy with bupropion
and either an SSRI, including three reports of seizure, for which in all cases
one or both agents were discontinued or dosages were decreased and adverse
events resolved. It is difficult to
determine whether P450-mediated drug interactions played a role in these
adverse reactions. However, the Sponsor
has provided a reference to 1 abstract7 in which 13 patients who
were on bupropion at doses of 150-450 mg/day had serum drawn before and after
12-60 days of
8
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