The median Tmax of dextromethorphan and bupropion when given as
AUVELITY was 3 hours and 2 hours, respectively.
The Cmax of the hydroxybupropion metabolite occurred approximately
3 hours post-dose and was approximately 14 times the peak level of
bupropion and its AUC0-12 was about 19 times that of bupropion. The
Cmax of the erythrohydroxybupropion and threohydroxybupropion
metabolites occurred approximately 4 hours post-dose and were
approximately equal to and 5 times that of bupropion, respectively. The
AUC0-12 values were 1.2 and 7 times that of bupropion, respectively.
Effect of Food
AUVELITY can be taken with or without food. Dextromethorphan Cmax
and AUC0-12 were unchanged and decreased by 14%, respectively,
and bupropion Cmax and AUC0-12 were increased by 3% and 6%,
respectively, when AUVELITY was administered with food.
Distribution
The plasma protein binding of dextromethorphan is approximately
60-70% and bupropion is 84%. The extent of protein binding of
the hydroxybupropion metabolite is similar to that for bupropion;
whereas, the extent of protein binding of the threohydroxybupropion
metabolite is about half that seen with bupropion.
Elimination
Following 8 days of administration of AUVELITY in extensive
metabolizers, the mean elimination half-life of dextromethorphan
was increased approximately 3-fold to 22 hours, as compared to
dextromethorphan given without bupropion.
The mean elimination half-life of dextromethorphan and bupropion
was 22 hours and 15 hours, respectively. The apparent elimination
half-life of hydroxybupropion, erythrohydroxybupropion and
threohydroxybupropion metabolites were approximately 35, 44 and
33 hours, respectively.
Metabolism
Dextromethorphan is primarily metabolized by CYP2D6 to
dextrorphan. bupropion is extensively metabolized with three active
metabolites: hydroxybupropion, which is formed via hydroxylation of
the tert-butyl group of bupropion, and the amino-alcohol isomers,
threohydroxybupropion and erythrohydroxybupropion, which are
formed via reduction of the carbonyl group. In vitro findings suggest
that CYP2B6 is the principal isoenzyme involved in the formation
of hydroxybupropion, while cytochrome P450 enzymes are not
involved in the formation of threohydroxybupropion. Oxidation of the
bupropion side chain results in the formation of a glycine conjugate
of meta-chlorobenzoic acid, which is then excreted as the major
urinary metabolite. The potency and toxicity of the metabolites
relative to bupropion have not been fully characterized. However, it
has been demonstrated in an antidepressant screening test in mice
that hydroxybupropion is one-half as potent as bupropion, while
threohydroxybupropion and erythrohydroxybupropion are 5-fold less
potent than bupropion.
Excretion
In CYP2D6 extensive metabolizers, approximately 37-52% of the
orally administered dose of dextromethorphan is recovered in
the urine. Less than 2% of the administered dose is excreted as
unchanged parent drug in the urine. In CYP2D6 poor metabolizers,
approximately 45-83% of the administered dose is recovered in the
urine. Approximately 26% of the administered dose is excreted as
unchanged parent drug in the urine.
Following oral administration of 200 mg of 14C-bupropion in
humans, 87% and 10% of the radioactive dose were recovered in
the urine and feces, respectively. Only 0.5% of the oral dose was
excreted as unchanged bupropion.