CLINICAL PHARMACOLOGY
Mechanism of Action:
The mechanism by which felbamate exerts its
anticonvulsant activity is unknown, but in animal test systems
designed to detect anticonvulsant activity, felbamate has
properties in common with other marketed anticonvulsants.
Felbamate is effective in mice and rats in the maximal
electroshock test, the subcutaneous pentylenetetrazol seizure
test, and the subcutaneous picrotoxin seizure test. Felbamate
also exhibits anticonvulsant activity against seizures induced
by intracerebroventricular administration of glutamate in rats
and N-methyl-D,L-aspartic acid in mice. Protection against
maximal electroshock-induced seizures suggests that felbamate
may reduce seizure spread, an effect possibly predictive of
efficacy in generalized tonic-clonic or partial seizures.
Protection against pentylenetetrazol-induced seizures suggests
that felbamate may increase seizure threshold, an effect
considered to be predictive of potential efficacy in absence
seizures.
Receptor-binding studies in
vitro indicate that felbamate has weak inhibitory
effects on GABA-receptor binding, benzodiazepine receptor
binding, and is devoid of activity at the MK-801 receptor
binding site of the NMDA receptor-ionophore complex. However,
felbamate does interact as an antagonist at the
strychnine-insensitive glycine recognition site of the NMDA
receptor-ionophore complex. Felbamate is not effective in
protecting chick embryo retina tissue against the neurotoxic
effects of the excitatory amino acid agonists NMDA, kainate, or
quisqualate in vitro.
The monocarbamate, p-hydroxy, and 2-hydroxy metabolites
were inactive in the maximal electroshock-induced seizure test
in mice. The monocarbamate and p-hydroxy metabolites had only
weak (0.2 to 0.6) activity compared with felbamate in the
subcutaneous pentylenetetrazol seizure test. These metabolites
did not contribute significantly to the anticonvulsant action of
felbamate.
Pharmacokinetics:
The numbers in the pharmacokinetic section are mean
± standard deviation.
Felbamate is well-absorbed after oral administration.
Over 90% of the radioactivity after a dose of 1000 mg
14 C felbamate was found in the urine. Absolute
bioavailability (oral vs. parenteral) has not been measured. The
tablet and suspension were each shown to be bioequivalent to the
capsule used in clinical trials, and pharmacokinetic parameters
of the tablet and suspension are similar. There was no effect of
food on absorption of the tablet; the effect of food on
absorption of the suspension has not been evaluated.
Following oral administration, felbamate is the
predominant plasma species (about 90% of plasma
radioactivity). About 40-50% of absorbed dose appears
unchanged in urine, and an additional 40% is present as
unidentified metabolites and conjugates. About 15% is
present as parahydroxyfelbamate, 2-hydroxyfelbamate, and
felbamate monocarbamate, none of which have significant
anticonvulsant activity.
Binding of felbamate to human plasma protein was
independent of felbamate concentrations between 10 and 310
micrograms/mL. Binding ranged from 22% to 25%,
mostly to albumin, and was dependent on the albumin
concentration.
Felbamate is excreted with a terminal half-life of 20-23
hours, which is unaltered after multiple doses. Clearance after
a single 1200 mg dose is 26±3 mL/hr/kg, and after
multiple daily doses of 3600 mg is 30±8 mL/hr/kg. The
apparent volume of distribution was 756±82 mL/kg after
a 1200 mg dose. Felbamate Cmax and AUC are proportionate to dose
after single and multiple doses over a range of 100-800 mg
single doses and 1200-3600 mg daily doses. Cmin (trough) blood
levels are also dose proportional. Multiple daily doses of 1200,
2400, and 3600 mg gave Cmin values of 30±5,
55±8, and 83±21 micrograms/mL (N=10 patients).
Linear and dose proportional pharmacokinetics were also observed
at doses above 3600 mg/day up to the maximum dose studied of
6000 mg/day. Felbamate gave dose proportional steady-state peak
plasma concentrations in children age 4-12 over a range of 15,
30, and 45 mg/kg/day with peak concentrations of 17, 32, and 49
micrograms/mL.
The effects of race and gender on felbamate
pharmacokinetics have not been systematically evaluated, but
plasma concentrations in males (N=5) and females (N=4) given
felbamate have been similar. The effects of felbamate kinetics
on hepatic functional impairment have not been evaluated.
Renal Impairment:
Felbamate's single dose monotherapy pharmacokinetic parameters
were evaluated in 12 otherwise healthy individuals with renal
impairment. There was a 40-50% reduction in total body
clearance and 9-15 hours prolongation of half-life in renally
impaired subjects compared to that in subjects with normal renal
function. Reduced felbamate clearance and a longer half-life
were associated with diminishing renal function.
Pharmacodynamics:
Typical Physiologic
Responses:
1. Cardiovascular: In adults, there is no effect of
felbamate on blood pressure. Small but statistically significant
mean increases in heart rate were seen during adjunctive therapy
and monotherapy; however, these mean increases of up to 5 bpm
were not clinically significant. In children, no clinically
relevant changes in blood pressure or heart rate were seen
during adjunctive therapy or monotherapy with felbamate.
2. Other Physiologic
Effects: The only other change in vital signs was
a mean decrease of approximately 1 respiration per minute in
respiratory rate during adjunctive therapy in children. In
adults, statistically significant mean reductions in body weight
were observed during felbamate monotherapy and adjunctive
therapy. In children, there were mean decreases in body weight
during adjunctive therapy and monotherapy; however, these mean
changes were not statistically significant. These mean
reductions in adults and children were approximately 5% of the
mean weights at baseline.
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