|
NDA 20-358 |
15 |
enough data to say that the antidepressant action of
B is mediated primarily through noradrenergic pathways. Although it was said that B was 3-4 x less
potent in inhibiting DA (vs NE) firing rate, it is not clear if a time vs
response analysis was done. i.e., the relative potency may have been different
at different times after dosing.
Furthermore, it was previously shown that the effectiveness of B in the
Porsolt test was dependent on dopaminergic, but not noradrenergic, neurons (My
original review of NDA 18-644). Also,
although a relatively weak blocker of neurotransmitter re-uptake, B is more
potent against DA uptake than against NE uptake both in vitro and
in vivo (although a table in submission of 1/28/93 to NDA 18-644
indicates that metabolites 306U73 and 494U73 are somewhat more potent against
NE [vs DA] in vitro).
Also, according to the latter submission there is a study showing that B
at a relatively low dose (10 mg/kg i.p.) increased extracellular DA
concentration in rat nucleus accumbens.
(NE apparently not studied).
Thus, while some of the above results indicate an
effect on noradrenergic and/or dopaminergic activity (also, efficacy in the
tetrabenazine test per se indicates such activity, as well as the
finding of beta-receptor down regulation [although not all studies have found
the latter], it is premature to assert the primacy of noradrenergic
activity. An appropriate statement in
the labelling might be (assuming the data on decreased firing rate has or will
be submitted and is adequate):
“The neurochemical mechanism of the antidepressant
effect of bupropion is not know.
Bupropion is a relatively weak blocker of the neuronal uptake of
norepinephrine, serotonin, and dopamine, and does not inhibit monoamine
oxidase; however there is some evidence to suggest that its antidepressant
action is mediated by noradrenergic and/or dopaminergic mechanisms.”
b)
Second
and third paragraphs
The sponsor wishes to add statements that B
administered to mice in a sustained release formulation produced less of an
increase in motor activity and fewer convulsions that when administered in an
immediate release formulation. The data
supporting this are shown in attached tables.
Although these data are relatively minimal (e.g., only a single dose was
used for the locomotor activity study), these statements are acceptable. (However, the term “significantly” should be
removed from both statements; statistical significance is implied by the
declaration of an effect). (One might
expect that the reason for these pharmacological differences was due to
differences in PK between formulations; however as shown in the attached
figures there appeared to be little difference in plasma levels of B and
metabolites between the 2 formulations.
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