MEMORANDUM Department of Health and Human Services
Public Health Service
Food and Drug Administration
Center for Drug Evaluation and Research
DATE: March
6, 1996
FROM: Thomas
P. Laughren, M.D. (initialed)
Group Leader, Psychiatric
Drug Products
Division
of Neuropharmacological Drug Products
NFD-120
SUBJECT: Proposed Changes to Approvable
Letter and Draft Labeling for
Wellbutrin (bupropion) SR
THROUGH: Paul Leber, M.D.
Director,
DNDP (HFD-120)
TO: Robert
Temple, M.D.
Director,
ODE-I (HFD-101)
We’ve
made virtually all of the changes proposed in the returned package.
The
following are responses to questions:
Bupropion/Metabolites
Pharmacokinetics (p. 3):
Question: Why is there so much accumulation for the
metabolites given that they have t1/2’s similar to the parent:
The
likely reason for the much higher levels of metabolite compared to parent is
less efficient clearance and smaller volumes of distribution for the
metabolites compared to the parent.
T1/2 is directly proportional to volume of distribution and inversely
proportional to clearance i.e., t1/2 ≈ V/Cl. Thus, a smaller V associated with a smaller
Cl for metabolites would give the same t1/2 as for the parent. Metabolites are often more polar than parent
compound and therefore less widely distributed.
You
have cast the question in terms of accumulation, however, it isn’t clear to me
that it’s meaningful to consider accumulation ratio for metabolite when it is
parent drug that is being administered.
In any case, I don’t think it’s a problem of mismatch between t1/2 and
dosing interval (the only determinants of accumulation); rather, the excess of
metabolite is there from the first dose, and the likely basis for the higher
observed metabolite levels is inefficient clearance.
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