4.1.4
What efficacy and safety information contributes to the
assessment of clinical pharmacology and biopharmaceutics study data (e.g., can
disparate efficacy measurements or adverse events reports to be attributed to
intrinsic or extrinsic factors that alter drug exposure/response relationships
in patients)?
The
present submission did not include clinical efficacy trials. Exposure-related adverse effects include
seizures, with a 10-fold increase in seizure incidence compared to 300 mg per
day at doses between 450 and 600 mg per day of the immediate-release
formulation of bupropion, according to information provided in the label of WELLBUTRIN
SR. The present submission did not
evaluate dose-dependence of adverse effects.
The studies were conducted in healthy volunteers without clinically
significant impairment in factors that could alter exposure-response relations
(such as renal or hepatic impairment, congestive heart failure, age, or
concomitant medications).
4.2
General Clinical Pharmacology
4.2.1 What is the basis for selecting the response
endpoints, i.e., clinical or surrogate endpoints, or biomarkers (also called
pharmacodynamics, PD) and how are they measured in clinical pharmacology and
clinical studies.
The
present submission did not include studies evaluating pharmacodynamic response
to WELLBUTRIN XL.
Although
the mechanism of action of bupropion as an antidepressant is unknown, it
inhibits dopamine uptake and this could be due to occupancy of the dopamine
transporter. The present submission
included a positron emission tomography (PET) study (OHB10001) to evaluate
relationship between dopamine transporter occupancy and bupropion and
metabolites concentration at steady state following administration of bupropion
given as 150 mg WELLBUTRIN SR twice daily for 8 days in 6 healthy male
volunteers, mean age 30.7 (23-39) years of age. This is a clinically relevant dose. The full study report can be found in the Appendix, Section
6.2.1. PET studies demonstrated
approximately 26% occupancy of the dopamine transporter in the striatum up to
24 hours following the last dose of bupropion.
Future efforts would be required to characterize he relationship between
occupancy and clinical effort, in order to provide a link between dose,
pharmacokinetics, and effect as well as to further characterize the mechanism
for the effect.
4.2.2
Are the active moieties in the plasma (or other biological fluid)
appropriately identified and measured to assess pharmacokinetic parameters and
exposure response relationships?
Bupropion
and its active metabolites hydroxybupropion, threohydrobupropion, and erthyrohydrobupropion
[erythrohydrobupropion] were appropriately
identified and measured in the plasma.
Please refer to the Bioanalytical Section (4.6). In addition to evaluating the PK of
bupropion and its metabolites, the Pharmacological Activity-Weighted Composite
(PAWC) of bupropion and its metabolites were determined and evaluated. Bupropion and its metabolites were
previously used in approval of WELLBUTRIN SR tables since approximately 90% of
systemic exposure is due
10
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