44 weeks of maintenance treatment.  The offset of the pharmacological response is not described in the summary material provided by the sponsor.

 

·         Are the dose and dosing regimen consistent with the known relationship between dose-concentration-response, and are there any unresolved dosing or administration issues?

 

A dose-response relationship for bupropion as an antidepressant has not been well-characterized.  In comparison with the proposed dosing of WELLBUTRIN XL, the usual adult target dose for WELLBUTRIN SR is 300 mg/day (given as 150 mg twice daily), and doses of 400 mg mg/day may be considered.  The target dose of WELLBUTRIN is also 300 mg/day (given as 100 mg three times daily), with a maximum dose of 450 mg/day in patients who do not have an adequate clinical response.

 

The once daily dosage regimen for WELLBUTRIN XL is consistent with its extended release profile and long elimination half-life.

 

4.2.4        What are the basic pharmacokinetic parameters after administration of WELLBUTRIN XL and how does the PK of the drug and its major active metabolites in healthy volunteers compare to that in patients?

 

According to summary information provided by the sponsor, after administration of bupropion given as immediate release WELLBUTRIN to healthy volunteers the mean apparent oral clearance (Cl/F) was 200 L/hr and the volume of distribution (Vd/F) was 700 L, and the mean elimination half-life was approximately 20 hours.  After steady state dosing of this formulation the t_max of bupropion was approximately 1.5 hours, while the t_max for the active metabolites was approximately 3-4 hours.

 

In the data submitted for the present NDA, following a single dose of 300 mg of WELLBUTRIN XL, the t_max for bupropion was approximately 5 hours and the t_max for the active metabolites was approximately 8-16 hours (Study AK1BIOVAIL2571).  The mean elimination half-life was approximately 22 hours.  After steady state dosing of this formulation (300 mg once daily) the t_max of bupropion was approximately 5 hours and the t_max of the active metabolites was approximately 6-8 hours.  After both single and multiple dosing, most of the exposure was from the metabolites as has been previously reported for other formulations, and the mean c_max of hydroxybupropion was approximately 7 times higher and the AUC_0-24 was approximately 13 times higher than the respective values of the parent compound.  The Metabolite/Parent ratio (metabolite AUC/molecular weight)/(bupropion AUC/molecular weight), with AUC_0-∞ for hydroxybupropion.  More complete information on the pharmacokinetic parameters after single and multiple doses can be found in Sections 4.5.6 and 4.5.7, respectively.

 

The pharmacokinetic behavior of WELLBUTRIN XL has not been evaluated in the target population.

 

It has been previously demonstrated that bupropion is extensively metabolized in humans.  According to the labeling for WELLBUTRIN SR, following oral administration of [¹⁴C]-

 

 

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