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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