CLINICAL PHARMACOLOGY
In controlled clinical trials, carbamazepine has been shown to be
effective in the treatment of psychomotor and grand mal seizures, as well as
trigeminal neuralgia.
Mechanism of Action
Carbamazepine has demonstrated anticonvulsant properties in rats
and mice with electrically and chemically induced seizures. It appears to act by
reducing polysynaptic responses and blocking the post-tetanic potentiation.
Carbamazepine greatly reduces or abolishes pain induced by stimulation of the
infraorbital nerve in cats and rats. It depresses thalamic potential and bulbar
and polysynaptic reflexes, including the linguomandibular reflex in cats.
Carbamazepine is chemically unrelated to other anticonvulsants or other drugs
used to control the pain of trigeminal neuralgia. The mechanism of action
remains unknown.
The principal metabolite of carbamazepine, carbamazepine-10,11-epoxide, has
anticonvulsant activity as demonstrated in several in
vivo animal models of seizures. Though clinical activity for the epoxide
has been postulated, the significance of its activity with respect to the safety
and efficacy of carbamazepine has not been established.
Pharmacokinetics
Carbamazepine (CBZ): Taken every 12
hours, carbamazepine extended-release capsules provide steady state plasma
levels comparable to immediate-release carbamazepine tablets given every 6
hours, when administered at the same total mg daily dose.
Following a single 200 mg oral extended-release dose of carbamazepine, peak
plasma concentration was 1.9 ± 0.3μg/mL and the time to reach the peak was 19 ±
7 hours. Following chronic administration (800 mg every 12 hours), the peak
levels were 11.0 ± 2.5 μg/mL and the time to reach the peak was 5.9 ± 1.8 hours.
The pharmacokinetics of extended-release carbamazepine is linear over the single
dose range of 200-800 mg.
Carbamazepine is 76% bound to plasma proteins. Carbamazepine is primarily
metabolized in the liver. Cytochrome P450 3A4 was identified as the major
isoform responsible for the formation of carbamazepine-10,11-epoxide. Since
carbamazepine induces its own metabolism, the half-life is also variable.
Following a single extended-release dose of carbamazepine, the average half-life
range from 35-40 hours and 12-17 hours on repeated dosing. The apparent oral
clearance following a single dose was 25 ± 5 mL/min and following multiple
dosing was 80 ± 30 mL/min.
After oral administration of14C-carbamazepine, 72% of
the administered radioactivity was found in the urine and 28% in the feces. This
urinary radioactivity was composed largely of hydroxylated and conjugated
metabolites, with only 3% of unchanged carbamazepine.
Carbamazepine-10,11-epoxide (CBZ-E):
Carbamazepine-10,11-epoxide is considered to be an active metabolite of
carbamazepine. Following a single 200 mg oral extended-release dose of
carbamazepine, the peak plasma concentration of carbamazepine-10,11-epoxide was
0.11± 0.012 μg/mL and the time to reach the peak was 36 ± 6 hours. Following
chronic administration of a extended-release dose of carbamazepine (800 mg every
12 hours), the peak levels of carbamazepine-10,11-epoxide were 2.2± 0.9 μg/mL
and the time to reach the peak was 14 ± 8 hours. The plasma half-life of
carbamazepine-10,11-epoxide following administration of carbamazepine is 34 ± 9
hours. Following a single oral dose of extended-release carbamazepine (200-800
mg) the AUC and Cmax of carbamazepine-10,11-epoxide were
less than 10% of carbamazepine. Following multiple dosing of extended-release
carbamazepine (800-1600 mg daily for 14 days), the AUC and Cmax of carbamazepine-10,11-epoxide were dose related, ranging
from 15.7 μg.hr/mL and 1.5μg/mL at 800 mg/day to 32.6 μg.hr/mL and 3.2μg/mL at
1600 mg/day, respectively, and were less than 30% of carbamazepine.
Carbamazepine-10,11-epoxide is 50% bound to plasma proteins.
Food Effect: A high fat meal diet increased the rate
of absorption of a single 400 mg dose (mean Tmax was
reduced from 24 hours, in the fasting state, to 14 hours and Cmax increased from 3.2 to 4.3 μg/mL) but not the extent (AUC)
of absorption. The elimination half-life remains unchanged between fed and
fasting state. The multiple dose study conducted in the fed state showed that
the steady-state Cmax values were within the therapeutic
concentration range. The pharmacokinetic profile of extended-release
carbamazepine was similar when given by sprinkling the beads over applesauce
compared to the intact capsule administered in the fasted state.
Special Populations
Hepatic Dysfunction: The effect of
hepatic impairment on the pharmacokinetics of carbamazepine is not known.
However, given that carbamazepine is primarily metabolized in the liver, it is
prudent to proceed with caution in patients with hepatic dysfunction.
Renal Dysfunction: The effect of renal impairment on
the pharmacokinetics of carbamazepine is not known.
Gender: No difference in the mean AUC and Cmax of carbamazepine and carbamazepine-10,11-epoxide was found
between males and females.
Age: Carbamazepine is more rapidly metabolized to
carbamazepine-10,11-epoxide in young children than adults. In children below the
age of 15, there is an inverse relationship between CBZ-E/CBZ ratio and
increasing age.
Race: No information is available on the effect of
race on the pharmacokinetics of carbamazepine.
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