plasma concentrations are higher, and the metabolites account for approximately 90% of the exposure following administration of bupropion.

 

4.6.3        For all moieties measured, is free, bound or total measured?  What is the basis for that decision, if any, and is it appropriate?

 

For all moieties measured, the total is measured.  According to the label for WELLBUTRIN SR, bupropion is 84% bound to human plasma proteins at concentrations up to 200 µg/ml, with similar protein binding for hydroxybupropion.  The extent of protein binding of threoamino alcohol is half that seen with bupropion.  Since previous evaluations of bupropion and its metabolites have measured total levels, it is acceptable to continue to measure total concentrations, allowing for inter-study comparisons.

 

4.6.4        What bioanalytical methods are used to assess concentrations?

 

·         What is the range of the standard curve and how does it relate to the requirements for the clinical studies?

 

Linearity was established in the range of [blacked out] for bupropion, erythroamino alcohol, threoamino alcohol, and hydroxybupropion, respectively in the method used for the BE studies reviewed for the present NDA.  The endpoints of these ranges (the LLOQ and ULOQ) bracket the range of plasma concentrations observed in the pharmacokinetic studies that were evaluated.

 

·         Is the bioanalytical method adequately documented and validated?

 

The bioanalytical method is adequately documented and validated, and the performance of the assays for the clinical pharmacology studies is considered acceptable.

 

 

Stamped: Appears This Way On Original

 

 

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