NDA 20-358

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a)       Liver

 

Increased incidence of hepatocellular hypertrophy, with incidence as follows:

 

 

C

HD

HD*

TERMINATION

0/19

16/17

12/13

DEATHS/SAC.

0/1

3/3

3/7

 

This findings was not seen in the 2 LD found dead and 1 MD prematurely sacrificed which were examined (nut note these exams occurred relatively early in the treatment period).  It was described as “minimal; centrilobular” in all animals.  Liver was not examined in recovery animals.

 

b)       Kidney

 

Increased incidence of chronic progressive nephrosis in males, with incidence as follows:

 

 

C

HD

HD*

TERMINATION

3/10

6/8

6/7

DEATHS/SAC.

0/0

0/2

3/3

RECOVERY

¼

4/4

4/4

 

 

It was not found among the 2 LD M found dead (but note these deaths occurred relatively early in the treatment period).  The severity ranged from very minimal to mild.

 

12)    PK Data

 

Plasma levels of bupropion and 3 metabolites (306U73, 494U73, and 17U67) were assayed pre-dosing and at 0.5, 1, 2, and 4 hr. post-dosing on days 10 and 82 in 3 (sometimes 2)/sex/group/time point.  (Exception = the 1 hr. point not done day 82).  Results fro bupropion and 306U73 are summarized in the attached 2 tables (day 10 and 82, resp.)  (Compound 494U73 was present in only a few samples.  Values for 17U67 were not given although it was stated that, as for 494U73, the data for 17U67 were insufficient to permit calculation of PK parameters.  From the tables it would appear that:

 

1)       Plasma levels (of both parent and metabolite) were generally not dose-related (except perhaps in F on day 82).

 

 

 


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