·         Can the 150 and 300 mg strength tablets be combined to achieve the maximum recommended daily dose of 450 mg?

 

It has previously been demonstrated that the pharmacokinetics of bupropion and its metabolites are linear following chronic administration of 300 to 450 mg/day.  The present NDA has demonstrated dosage strength equivalence of the 150 mg and 300 mg tablets.  Therefore, the 150 mg and 300 mg tablets can be combined to achieve the maximum recommended dose of 450 mg daily.

 

4.5.8        If unapproved products or altered approved products were used as active controls, how is BE to the approved product demonstrated?  What is the basis for using either in vitro or in vivo data to evaluate BE?

 

The only product used was the already approved WELLBUTRIN immediate release tablet.

 

4.5.9        What other significant, unresolved issues related to in vitro dissolution or in vivo BA and BE need to be addressed?

 

A DSI inspection of study AK1BIOVAIL2543, the pivotal BE study, has been requested and the results are pending.

 

4.5.10    If replicate design studies were conducted and individual BE was analyzed, what were the outcomes with respect to variability and subject-by-formulation interactions?

 

These studies were not conducted for WELLBUTRIN XL.

 

 

4.6         Bioanalytical Method

4.6.1        How are the active moieties identified and measured in the plasma in the clinical pharmacology and biopharmaceutics studies?

 

A liquid chromatography [blacked out] mass spectrometry (LC-MS/MS) assay was used for analysis of bupropion and its metabolites bupropion erythroamino alcohol, bupropion threoamino alcohol, and hydroxybupropion in human plasma.  A detailed description of the method is found in the Appendix, Section 6.2.5.

 

4.6.2        Which metabolites have been selected for analysis and why?

 

Bupropion as well as its metabolites bupropion erythroamino alcohol, bupropion threoamino alcohol, and hydroxybupropion have been selected for analysis.  These are active metabolites, and in animal models that screen for antidepressant activity show potencies after intraperitoneal injection that are 0.2, 0.2, 0.6 times that of bupropion, respectively, according to information provided by the Sponsor.  Although the relative potencies are lower than that of bupropion, the

 

 

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