3        Summary of Clinical Pharmacology and Biopharmaceutics Finding

 

3.3  Background

 

WELLBUTRIN XL tablets are extended release tablets for once daily administration that contain bupropion hydrochloride.  Bupropion is currently available as an antidepressant medication in other formulations, an immediate release tablet that is given 100 mg three times daily, and a sustained release (SR) formulation that is given twice daily.

 

The mechanism of action of bupropion as an antidepressant is unknown but is thought to be medicated by noradrenergic and/or dopaminergic mechanisms.  According to the Sponsor it inhibits neuronal reuptake of norepinephrine and dopamine and does not inhibit monoamine oxidase.

 

According to the WELLBUTRIN SR label, bupropion and its metabolites display linear kinetics with chronic administration of 300 to 405 mg/day.  Bupropion has an elimination half-life of approximately 22 hours.  It is extensively hepatically metabolized.  It has three active metabolites, hydroxybupropion, threohydrobupropion (bupropion threoamino alcohol), and erythrohydrobupropion (bupropion erythroamino alcohol) that account for approximately 90% of the exposure following administration of bupropion.  Its P450-mediated metabolism is primarily via CYP2B6.

 

3.2  Current Submission

 

The present NDA (21-515) has been submitted to support the approval of WELLBUTRIN XL for the treatment of major depressive disorder.  The strengths are 150 mg and 300 mg.  The proposed target dose is 300 mg/day given one daily.  It is recommended that dosing begin at 150 mg/day.  The maximum recommended dose is 450 mg/day.

 

Two studies were submitted but not reviewed by OCPB as they were pilot studies evaluating several different formulations of WELLBUTRIN XL tablets.  These studies were:

 

·         AK1BIOVAIL2526 -          Pilot bioequivalence of two candidate formulations

·         AK1BIOVAIL2544 -          Bioequivalence of discontinued formulation

 

In addition, Study OHB10001, a positron emission tomography study to evaluate dopamine transporter occupancy was reviewed, but not utilized in the Office of Clinical Pharmacology and Biopharmaceutics (OCPB) evaluation of the data submitted to support this NDA for this once a day formulation.

 

The following clinical pharmacology studies have been submitted and reviewed:

 

 

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