6.0
Summary of Human Pharmacokinetics
The
following is a very brief summary of bupropion sustained-release
pharmacokinetic data, which are reviewed separately.
Following
multiple-dose oral administration of bupropion immediate-release tablets to
healthy male volunteers, the drug and its basic metabolites were found to
exhibit linear kinetics over the range of 300 to 450 mg/day. In animal models, the three metabolites of
the immediate-release formulation (306U73, 494U73, and 17U87) are, respectively
0.568, 0.208, and 0.208 times as potent as the parent drug. The metabolites are thought to contribute
significantly to the therapeutic effect of bupropion because of their
relatively higher plasma concentrations.
Oral absolute bioavailability of bupropion in humans has not been
determined because an intravenous formulation for human use is not
available. In rats and dogs, the
absolute bioavailability of bupropion ranges from 5% to 20%. Bupropion is extensively metabolized in the
liver. Following oral administration of
the immediate-released formulation, time to peak plasma concentration is up to
two hours. The elimination half-life of
bupropion immediate release following single-dose administration is about 14
hours, with a range of 8 to 24 hours.
Bupropion is about 80% bound to human albumin at plasma concentrations
up to 200 µg/mL. Following oral
administration of 200 mg 14C-bupropion HCl aqueous solution in man,
87% and 10% of the radioactive dose was recovered in urine and feces,
respectively. The fraction of the oral
dose of bupropion excreted unchanged in urine was only 0.5%.
Following
single-dose oral administration of bupropion sustained-release tablets to
healthy male volunteers, peak plasma levels were achieved within three hours
for the parent compound and within six hours for its metabolites. Peak plasma levels of bupropion were about
50% of that for the immediate-release tablet when given in equal single
doses. At steady state, peak plasma
levels of bupropion sustained-release tablet given b.i.d. were about 15% lower
than that for the 100 mg immediate-release tablet given t.i.d. Peak levels of the metabolites were similar
following both the sustained and immediate-release tablets. Trough and average plasma levels of
bupropion and its metabolites for the 150 mg b.i.d. sustained-release tablet
were similar to those for the 100 mg t.i.d. immediate-release tablet. The 90% confidence intervals for the
geometric mean AUC over the whole 24-hour dosing interval for bupropion and its
three primary metabolites and the pharmacologic activity-weighted composite
fell within the range of equivalence criteria of 80% to 125% of the
immediate-release drug.
7.0
Efficacy
Findings
7.1
Overview
of Studies Pertinent to Efficacy
The
bupropion sustained-release NDA comprises reports of two phase 2-3 clinical
trials that were intended, for the most part, to explore antidepressant
efficacy of several different dosing levels of the drug. Studies 203 and 205 were both U.S.
placebo-controlled fixed dose studies.
One open trial of bupropion sustained-release was also conducted (Study
208), which will be reviewed below in brief.
7.2
Summary of Studies Pertinent to Efficacy
7.2.1
Study 203
7.2.1.1
Investigators and Location
Six
U.S.A. sites participated in this trial.
The principal investigators were L.A. Cummingham at the Vine Street
Clinic, Springfield, IL, L.F. Fabre at Research Testing, Inc., Houston, TX,
J.P. Feighner at the Feighner Research Institute, San Diego, CA, E.A. Gardner
of Washington, D.C., F.W. Reimherr at the University of Utah, Salt Lake City,
UT, and E.C. Settle, JR. and S.C. Lerfald of Charleston, WV.
Bupropion
Sustained-Release Clinical Review 11
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