Bupropion in humans, 87% of the radioactive dose was recovered in urine and 10% recovered in feces.

 

4.2.5        What is the inter-subject variability of PK parameters in volunteers and patients, and what are the major causes of variability?

 

In healthy volunteers, inter-subject variability after administration of single or multiple doses of 300 mg WELLBUTRIN XL in the bioequivalence and dosage strength equivalence studies (2543 and 2561, respectively) was approximately 25-32% for Cmax and 27-30% for AUC for bupropion.  For the metabolites the variability was approximately 23-37% for Cmax .  For AUC, inter-subject variability was approximately 29% for bupropion erythroamino alcohol and bupropion threoamino alcohol after multiple doses, and approximately 36-53% for hydroxybupropion after multiple doses and for all of the metabolites after single doses.  Variability could be due to large interindividual differences in expression of CYP2B6, the P450 isozyme that is involved in the formulation of hydroxybupropion, as well as variability in expression of other enzymes involved in metabolism of bupropion that are not thought to be P450 enzymes.

 

4.3         Intrinsic Factors

 

4.3.1          What intrinsic factors (age, gender, race, weight, height, disease, genetic polymorphism, pregnancy, and organ dysfunction) influence exposure and/or response and what is the impact of any differences in exposure on the pharmacodynamics?

 

The pharmacokinetics of bupropion have been previously studied in special populations and the influence on exposure can be found in the label of WELLBUTRIN SR (and repeated in the proposed label for WELLBUTRIN XL) as outlined below.

 

Elderly – A single and multiple dose study has suggested that elderly are at increased risk of exposure to bupropion and its metabolites.

 

Pediatrics – The immediate release formulation of bupropion has been studied in pediatrics and was well tolerated, but limited exposure was considered insufficient to assess the safety of bupropion in pediatrics.

 

Gender – A single dose study did not reveal a sex-related difference in the PK parameters of bupropion.

 

Race – Evaluation of the effect of race on bupropion pharmacokinetics is not described in the labeling of WELLBUTRIN SR or in the proposed labeling of WELLBUTRIN XL.

 

Renal Impairment – The effect of renal disease on the pharmacokinetics of bupropion ha not been studied, although the elimination of the major metabolites may be affected by reduced renal function.

 

Hepatic Impairment – The half-life of hydroxybupropion is significantly longer in patients with alcoholic liver disease than in healthy volunteers, and the AUCs for bupropion and

 

 

 

13

 

 

Back a Page
Next Page
Back to Wellbutrin XL NDA Index Page
Back to Main Index Page