to metabolites, rather than parent drug.  It should be noted that the PAWC is a value that is calculated based on relative potency determined in an animal model of antidepressant activity, and does not represent pharmacologic activity in humans.

 

4.2.3        What are the characteristics of the exposure-response relationships (dose-response, concentration-response) for efficacy and safety?

·         Based on PK parameters, what is the degree of linearity or nonlinearity in the dose-concentration relationship for WELLBUTRIN XL?

 

According to the WELLBUTRIN SR label, bupropion and its metabolites display linear kinetics with chronic administration of 300 to 450 mg/day.  This relationship was studied in the present application.

 

·         Do PK Parameters change with time following chronic dosing?

 

The pharmacokinetic parameters have not been directly compared following acute and chronic dosing of WELLBUTRIN XL in the same study.  The following data summarizes comparable pharmacokinetic data from studies submitted to the present NDA (21-515) for WELLBUTRIN XL after single or multiple doses of 300 mg WELLBUTRIN XL.

 

Mean (% CV) Single Dose PK Parameters

(Study AK1BIOVAIL2571)

                                                tmax(h)a                                      AUC0-∞ (ng*h/ml)

Bupropion                                 5.00 (4.00 – 8.00)                      1728.3 (28)

Bupropion                                 16.00 (5.5.0 – 24.00)                 1613.6 (39)                  

Erythyroamino Alcohol             

Bupropion Threoamino               8.0 (5.00 – 16.00)                      9091.3 (43)

Alcohol

Hydroxybupropion                     12.00 (6.00 – 24.00)                  23498.8 (41)

PAWC                                     5.50 (4.50 – 24.00)                    70.4 (34)

                                               

                                                Mean (%CV) Multiple Dose PK Parameters

                                                (Study AK1BIOVAIL2543)

                                                tmax(h)a                                      AUC0-24 (ng*h/ml)

Bupropion                                 5.00 (3.00 – 7.00)                      1612.0 (30)

Bupropion                                 8.00 (5.00 – 14.00)                    2145.7 (29)                  

Erythyroamino Alcohol             

Bupropion Threoamino               8.00 (5.00 – 14.00)                    10987.9 (29)

Alcohol

Hydroxybupropion                     7.00 (4.00 – 14.00)                    20824.8 (36)

PAWC                                     6.00 (4.00 – 14.00)                    66.5 (27)

 amedium (range)

 

·         How long is the time to onset and offset of the pharmacological response or clinical endpoint?

 

According to the label for WELLBUTRIN SR, 4 weeks may be required before the full antidepressant effect is evident.  Efficacy of WELLBUTRIN SR was demonstrated for as long as

 

 

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