with
a 90% confidence interval of 0.76 to 0.85.
Since the majority of the exposure is due to the metabolites, and
bioequivalence is demonstrated with the metabolites, and for all other
parameters including Cmax and AUC bupropion, the two formulations
can be considered to be comparable in vivo. As previously noted 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.
Of
note, WELLBUTRIN SR 150 mg tablets were approved based on BE results for
the parent and 3 metabolites (NDA 20-358).
BE criteria in that case were net except for Cmax for the parent compound
(90% CI was [blacked out].
·
What dosing regimen changes are necessary, if any, in the presence or
absence of PK-PD relationship?
The once daily 300 mg WELLBUTRIN XL demonstrated comparable exposure to the immediate release product given as 100 mg three times daily as discussed above. Therefore, dosage regimen changes are not necessary.
It should be noted that although comparable exposure was demonstrated, there are differences in the shapes of the curves for bupropion in the WELLBUTRIN XL formulation compared with immediate release formulation. The clinical relevance of these differences cannot be predicted based on the pharmacokinetics. However, the comparable exposure and the role of the metabolites in the exposure and pharmacologic activity support the approval of the WELLBUTRIN XL formulation. Of note, for WELLBUTRIN SR, although there were also differences in the shapes of the plasma concentration curves compared to WELLBUTRIN IR, a clinical trial demonstrated efficacy of WELLBUTRIN SR in maintaining antidepressant response.
4.5.2
Based on BCS principles, in what class is this drug and
formulation? What solubility,
permeability and dissolution data support this classification?
BCS-based
waivers do not apply in the case of an extended release product.
4.5.3
What is the in vivo relationship of the proposed to be-marketed
formulation to the pivotal clinical trial formulation in terms of comparative
exposure?
This
NDA did not include a pivotal clinical trial.
The proposed to-be-marketed formulation is the same formulation that was
used in the bioequivalence studies except that the bioequivalence study dosages
strengths were not imprinted. The
imprinted tablets should meet the selected dissolution specifications. This has been referred to the Chemistry
reviewer.
4.5.4
What is the effect of food on the bioavailability (BA) of the drug from
the dosage form?
A
food effect study (AK1BIOAVAIL2548) evaluated the effect of food (a high fat
meal) on the oral bioavailability of bupropion after administration of
WELLBUTRIN XL 300 mg relative to
20
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