NDA
20-358: WELLBUTRIN® SR tablets
metabolites have been identified. They are the erythro- and threo-amino alcohols of bupropion (17U67 and 494U73, respectively), the erythro-amino diol of bupropion (287U73), and a morpholinol metabolite (306U73)
Bupropion
is about 84% bound to plasma albumin at plasma concentrations up to 200 µg/mL.
The
sponsor obtained the pharmacologic activity-weighted concentrations which were
determined at each sampling time point by multiplying the concentration of each
compound by its relative potency determined in animal studies based on ED50
(bupropion = 1.000, 306U73 = 0.568, 494U73 = 0.208, and 17U67 = 0.208) and
adding the four products.
Pharmacokinetic parameters for the pharmacologic activity-weighted
composite (PAWC) were also obtained.
However, it should be noted that PAWC is a theoretical value on doses
given to animals. It realistically
does not provide for a true representation of activity in humans.
Study
96: The steady-state
pharmacokinetic profiles of bupropion and its active metabolites (306U73, 494U73, and 17U67) were determined
in twenty two (22) healthy male volunteers after oral administration of IR
WELLBUTRIN® doses of 300 mg/day (as 100 mg of 6h, 6h, and 12h dosings)
and 450 mg/day (as 150 mg of 6h, 6h, and 12h dosings) for 10 days.
Steady
state plasma levels were achieved within 8 days for bupropion and its active
metabolites (306U73, 494U73, and 17U67).
After
chronic oral administration of bupropion, the peak plasma concentration for the
active metabolite, 306U73 was achieved within 3 hours and was about 12 times
the peak level of the parent drug.
Metabolite 494U73 showed a peak plasma concentration about 5 times the
peak level of bupropion. Finally,
17U67 metabolite showed similar peak levels as the parent drug, bupropion.
At steady
state, mean AUC0-6hr was about 17, 7, and 1.5 times larger for
306U73, 494U73, and 17U67, respectively, than for bupropion. Mean (±SD) elimination half-life (T1/2)
of bupropion. 306U73, 494U73 and
17U67 was 21 (9), 20 (5), 37 (13), and 33 (10) hours, respectively. Mean (±SD) oral clearance of bupropion
is 2.7 (0.7) L/hr/kg.
At
steady state, bupropion and its active metabolites (306U73, 494U73, and 17U67)
exhibit linear kinetics over the dosing range of 300 mg/day to 450 mg/day of
the parent drug, which covers the therapeutic range for the IR product.
The
% CV (%CV = SD/Mean*100) in the pharmacokinetic parameters ranged from 19-44%
for bupropion, 26-61% for 306U73, 31-41% for 494U73, and 26-65% for 17U67.
6
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