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CLINICAL PHARMACOKINETICS
OF CARBAMAZEPINE
Student’s Name Ghada Ebrahim
ID No. 9860160
Presented by: Dr. Rafiq Abou Shaaban
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 Intuoduction on carbamazepine

Pharmacological Action :.
 Table No. (1)

Dosage Forms and dosing :
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4
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Pharmacokinetics :
 Absorption
 Distribution
 Elimination
 Table No. (3)
 Table No. (4)
 Therapeutic and toxic plasma concentration .
 Bioavailabitity.
 Volume of distribution.
 Clearance.
 Half – life.
 Time to sample.

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 Table No. (2)

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Equations and questions .
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 Introduction on Carbamazepine:
Carbamazepine is an anticonvulsant compound that is structurally
similar to Tricyclic antidepressant agent used in trigeminal neuralgin
and complex Partial seizures.
 Pharmacological actions:
Table No. (1)
Trade name
Tegretol .
Type of drug
Anticonvulsant .
Indication
-Trigeminal Neuraligia
-Treatment of acute mania and prophylaxis in
bibolar Disorder
-With hepatic disease .
-Serious blood disorder
-With MAO inhibitor.
- Patient with known hyper sensitivity to
Carbamazepine
-Dizziness (mild) , drowsness (mild ) , nausea ,
vomiting .
-Less common or rare :
Headache , dry of mouth .
-CNS :CNS depression , coma , mydriasis
-Respiratory system :
= depression , pulmonary edema .
-Cardiovascular : tachycardia.
-GIT : nausea and vomiting .
-Treatment : no known specific antidote to
carbamazapine
-Bone marrow function :
WBC S leukopenia
-Hepatic function :
cardamazepine produce liver dysfunction
-Urinary retention and I.O.P
Urinary retention and I.O.P
- Occurance / of behavioral disorder : Produce
agitationor confusion .
-Seizure frequency : CARB will increase frequency
of genevelised convulsion .
Contra - indication
Side – effects .
Over dose
Precautions
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 Dosage Forms and Dosing:
Table No. (2)
Types
Suspension
Tablet
Extended
Capsule
Epilepsy
Adults:
100 mg / 4times daily
Adults:
200 mg / 2times daily
Adults:
200 mg / 2times daily
Adults:
100-200 mg / 2times
Children:
50 mg / 4times daily
Children:
100 mg / 2times daily
Up to 12 years:
Determine by Doctor
Up to 12 years:
100-200mg
Trigeminal Adults:
50 mg / 4times daily
Nuralgia
Adults:
100 mg / 2times daily
Adults:
200 mg / day
Adults:
100-200 mg once or
twice aday
Children:
100-200 mg once or
twice aday
Children:
Children:
Dose determine by Doctor Determine by Doctor
Note:
Release Extended Release
Tablet
Children:
By Doctor
 If you miss a dose of this medicine, take it as soon as possible.
 Don`t double the dose.
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 Pharmacokinetics
The pharmacokinetic parameters
of carbamazepine disposition are
similar in children and in adults;
however, there is a poor
correlation between dosage and
plasma
concentrations
of
carbamazepine in children. The
effects of race and gender on
carbamazepine pharmacokinetics
have not been systematically evaluated.
 Absorption:
Carbamazepine is slowly absorbed from the GI tract. Following chronic
oral administration of carbamazepine tablets, suspension, extended-release
tablets, or extended-release capsules, peak plasma concentrations are
reached in 4.5, 1.5, 3—12, or 4.1—7.7 hours, respectively. The oral
bioavailabilities of carbamazepine tablets and suspension reportedly are
equivalent, although the rate of absorption is faster for the suspension. The
bioavailability of the extended-release tablets is reportedly 89%of that of
the suspension, and the absorption of the extended-release tablets is
slightly slower than that of the conventional tablets. Peak plasma
concentrations of the drug are higher and trough concentrations are lower
for the suspension comparedwith tablets when the drug is administered
daily, but steady-state concentrations reportedly are comparable when the
suspension is administered in 3 divided doses daily and the tablets are
administered in 2 divided doses daily Following oral administration of
carbamazepine extended-release capsules or tablets every 12 hours, steadystate plasma carbamazepine concentrations were comparable to those
achieved with corresponding dosages of the conventional (immediaterelease) tablets every 6 hours. Although one manufacturer states that peak
plasma concentrations may be higher with chewable tablets than with
conventional tablets, a crossover study employing this manufacturer’s
tablets in adults with seizure disorders showed no such difference. In this
study, the oral pharmacokinetics, including bioavailability, and peak and
trough plasma concentrations, were comparable for conventional and
chewable tablets of the drug, although individual patients may have
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achieved somewhat higher concentrations for one or the other tablet
formulation.
Two to 4 days of therapy may be required to achieve steady-state plasma
concentrations. Although optimal therapeutic plasma concentrations
suitable for all patients have not yet been determined, therapeutic plasma
concentrations of carbamazepine (for both anticonvulsant effects and relief
of pain of trigeminal neuralgia) are usually 3—14 µg/mL. Some
investigators have noted that nystagmus frequently occurs when plasma
concentrations are greater than 4 µg/mL and that ataxia, dizziness, and
anorexiaoften occur when plasma concentrations are 10 µg/mL or greater.
There appears to be a wide variation in steady-state plasma concentrations
produced by specific daily dosages of carbamazepine (e.g., daily dosages
of 800 mg, 1.2 g, or 1.6 g may produceplasma concentrations of 2—10
µg/mL).
In one study, when carbamazepine extended-release capsules (Carbatrol®)
were administered as a single 400-mg dose with a high-fat meal, the rate,
but not the extent, of carbamazepine absorption was increased when
compared with administration of the capsules in the fasting state. Results
of a multiple-dose study of the extended-release capsules indicate that
when these capsules are administered after a meal, peak steady-state
plasma concentrations are within the therapeutic range. When the
extended-release capsules of carbamazepine (Carbatrol®) are broken and
the beads sprinkled over applesauce prior to administration, the
pharmacokinetic profile of the drug is similar to that following oral
administration of the intact capsule to fasting individuals. The
manufacturer of carbamazepine extended-release capsules states that the
elimination half-life of the drug does not differ substantially between
fasted and nonfasted conditions of administration.
 Distribution
Carbamazepine is widely distributed in the body; the drug has been
detected in CSF (approximately 15—22% of serum concentrations), the
brain (at autopsy), duodenal fluids, bile, and saliva. A major metabolite,
carbamazepine 10,11-epoxide, has also been detected in CSF.
Carbamazepine rapidly crosses the placenta (i.e., 30—60 minutes) and
accumulates in fetal tissues, with higher concentrations in the liver and
kidney than in brain and lungs. Carbamazepine and its epoxide metabolite
are distributed in breast milk. The ratio of the concentration in breast milk
to that in plasma is approximately 0.4 for the drug and 0.5 for the epoxide
metabolite.
In vitro studies indicate that at plasma concentrations of 1—50 µg/mL,
75—90% of the drug is bound to plasma proteins.
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 Elimination
Carbamazepine has a relatively long plasma half-life, variously reported to
be 8—72 hours. The variability results in part because carbamazepine can
induce its own metabolism; autoinduction of metabolism usually is
completed after 3—5 weeks of a fixeddosing regimen. The plasma half-life
generally ranges from 25—65 hours initially and from 12—17 hours with
multiple dosing.
The metabolic fate of carbamazepine has not been completely elucidated.
A major metabolic pathway appears to be oxidation by microsomal
enzymes in the liver (principally cytochrome P-450 isoform 3A4) to form
carbamazepine 10,11-epoxide (CBZ-E), which isalmost completely
metabolized
to
trans-10,11-dihydroxy-10,11-dihydrocarbamazepine
(trans-CBZ-diol) and excreted in urine mainly unconjugated. CBZ-E has
anticonvulsant activity in animals and potent analgesic activity in patients
with trigeminal neuralgia. CBE-E also has been implicated as contributing
to adverse neurologic effects of the drug. Carbamazepine is more rapidly
metabolized to CBZ-E in children than in adults. In children younger than
15 years of age, there is an inverse relationship between the CBZ-E/CBZ
ratio and increasing age; this ratio was reported to be 0.44 in children
younger than 1 year old and 0.18 in children 10—15 years of age.
Carbamazepine also undergoes aromatic hydroxylation to form 2hydroxycarbamazepine and 3-hydroxycarbamazepine. The pathway is not
clearly determined, but the drug also undergoes metabolism to form 9hydroxymethyl-10-carbamoyl-acridan. Carbamazepine and its metabolites
are excreted in urine. Only about 1—3% of the drug is excreted in urine
unchanged. Carbamazepine induces liver microsomal enzymes and thus
may accelerate its own metabolism and that of other concomitantly
administered drugs that are metabolized by these enzymes. (See Drug
Interactions.)
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DRUG –DRUG INTERACTION:
 Table No. (3)
contraindication
CARBAMAZEPINE/MONOAMINE OXIDASE INHIBITORS Severe
sever
CARBAMAZEPINE/MACROLIDE ANTIBIOTICS
CLOZAPINE/CARBAMAZEPINE
CONTRACEPTIVES,ORAL/CARBAMAZEPINE
PROPOXYPHENE; INH/CARBAMAZEPINE
PROTEASE INHIBITORS/CARBAMAZEPINE
THEOPHYLLINES/CARBAMAZEPINE Moderate
moderate
ANTICOAGULANTS/CARBAMAZEPINE
CARBAMAZEPINE/CALCIUM CHANNEL BLOCKERS
CARBAMAZEPINE/CIMETIDINE CARBAMAZEPINE/DANAZOL
CARBAMAZEPINE/SELECTED SSRI'S
CYCLOSPORINE/CARBAMAZEPINE DOXYCYCLINE/BARBITURATES;
CARBAMAZEPINE FELBAMATE/CARBAMAZEPINE
HALOPERIDOL/CARBAMAZEPINE LITHIUM/CARBAMAZEPINE
VALPROIC ACID/CARBAMAZEPINE
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 Table No. (4)
Pharmacokinetics
Bioavailability
Variable
Peak
plasma
level
60-80% 6 to
(tablets) hours
Plasma half life
Active
Elimination
metabolites
initially, 30 to 50
12 hours*
predominantly
important**
later, 12 to 17
extrarenal
hours*
*Carbamazepine induces its own metabolism, plasma half life
therefore
decreases.
**The active metabolite carbamazepine-10,11-epoxide has a half
life of 6 hours.
Dose
Admini Initial loading dose Maintenance dose
stration Dose
Interval
Dose Interval
major tonic100-200
200-400 8 to 12
Oral
12 hours
clonic seizure
mg
mg
hours*
trigeminal
200-400
Oral
100 mg
12 hours
12 hours
neuralgia
mg
Taken with meals! Increase dose slowly (by a maximum of 200
mg/day
after
1
week)!
*Slow release tablets (e.g. tegretol CR divitabs) are absorbed
with great delay and thus hardly cause side effects that can be
related to peak concentration levels and they are only taken twice
a day.
Indication
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 Therapeutic and toxic plasma concentrations:
The range of therapeutic serum concentrations for
carbamazepine is 4 to 12 mg/1 . Many patients , however will
develop symptoms of toxicity when plasma concentration
exceed 9 mg/L for this reason, many clinicians prefer to use a
therapeutic range of approximately 4 to 8 mg/L the most
common adverse effects associated with carbamazepine
involve the central nervous system (CNS) nystagmus, ataxia ,
blurred vision, and drowsiness. In most patients, the ratio of
carbamazepine to its major metabolite(10-11-epoxide) is
relatively constant under certain conditions, however, such as
when felbamate is added to a patient’s carbamazepine regimen,
the carbamazepine concentrations reduced and the 10,11epoxside concentration is increased.
This may explain the observation of CNS side effects in some
patientswith relatively how carbamazepine concentrations there
are a number of dermatologic and hematologic side effects that
are not dose realated, the most serious of which are the rare,
but potentially fatal aplastic anemia and stevens johnson
syndrome in the early 1970 s concern about the serious
hematologic side effects limited the use of carbamazepoine
however , serious adverse hematologic effects appear to be
rare, although a mild leukopenia may occur .

Bioavailability(F):
Carbaazepine is a lipid souuble compound which is slowly
and variably absorbed from the gastrointestinal tract. Peak
plasma concentrations occur aporxximately six hours (range :2
to 24 hours) after oral ingestion although the bioavailability of
carbazmazepine has not been directly determined, it is
estimated to be greater than 70% and approach 100% . since
carbamazepine is so slowly absorved, changes in
gastrointestinal functions, especially those associated with
rapid transit, could decrease its bioavailability and result in
variable plasma concentrations of carbamazepine if
bioavailaillity is assumed to be 100% and absorption is in
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actuality less than complete ion patients with altered
gastrointestinal function there will be proportional errors in the
calculation of plasma concentrations,clearance and volume of
distribution for approximately 0.8 for carbamazepine when
administered as the oral tablet, chewable tablet, or suspension.
 Volume of distribution (Vd):
On average, the volume of distribution for carbamazepine is
approximately 1.4 L/kg. Although there is a wide range of
reported values (0.8 to 1 .9 L/kg) . this variabillity is probably
due to alteratios in plasma binding and calculation of the
volume of distribution from oral administration data.
Carbamazepine, a neutral compound that is primarily bound to
albumin and a-acid glycprorotein, has a free fraction (alpha) of
approximately 0.2 to 0.3. Although carbamazepine has
relatively significant binding to plasma proteins there are very
few clinical studies exploring alterations in plasma binding
characteristics. This may be because carbamzepine is bound to
multiple plasma proteins and with a free fraction of 0.2 to 0.3,
fairly large changes in plasma binding would be required for
the change in binding to become clinically significant.
 Clearance (CL):
Carbamazepine is eliminated almost exclusively by the
metabolic route, with less than 2% of an oral dose being
excreted unchanged in the urine . clearance values are difficult
to estimate because bioavailability is uncertain.Nevertheless,
the average clearance value appears to be approximately
0.064L/hr/kg in patients who have received the drug
chronically. In patients who are taking other enzyme inclucing
antiepileptic. Drugs concurrently, the clearance is increased to
approximately 0.1 L/kg/hr. single –dose studies is impractical
in the calculation of a maintenance dose.
The auto-induction of carbamazapine metabolism has many
clinical implications. It is important to initiate patients on
relatively low doses to avoid side effects early in the therapy.
The maintenance dose can be increased at one to two weeks
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intervals. The auto-induction phenomenon also limits
pharmacockinetic manipulation of carbamazepine dosing. For
example it is uncertain whether induction is an all-or-non or
graded process which is dose related. While most clinicians
assume that induction is complete within five to seven days, it
is possible that the majority of induction occurs over the first
one to three days. Finally, auto-induction of metabolism
commonly cause changes in steady-state carbamazepine levels
which are less than proportional to an increase in the
maintenance dose.
As with many of the anticonsulvant agents, carbamazepine has
been associated with cross-induction (i.e, enhanced
metabolism) of other anticonvulsants. For this reason,
whenever carbamazepine is added to an anticonvulsant
regimen, or other agents are added to a carbamazepine
regimen, additional plasma level monitoring may be
appropriate to ensure that the maintenance regimen continues
to result in plasma levels that are optional for therapeutic
control.
There is one report of a disproportionately large increase in
steady state plasma concentrations of carbamazepine may
undergo capacity-limited metabolism. It would be extremely
difficult to predict the out come of a dose adjustment if one had
to consider capacity-limited metabolism as well as induction of
metabolism.
 Half - life(t ½)
to Although single-dose studies predict a carbamazepine halflife of approximately
30 to 35 hours, steady-state datd suggest a half-life of
approximately 15 hours in patients receiving cabamazepine
monotherapy, and approximately 10 hours in patients receiving
other enzyme-inducing antiepileptic drugs(e.g, phenytoin,
phenobrabital) concurrently. Due to the auto-induction of
carbamazepine, pharmacockinetic date derived from singledose studies should not be used to calculate maintenance
regimens.
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 Time to sample
Obtaining carbamazepine plasma samples within the first few
weeks of therapy may be useful to establish a relationship
between carbamazepine concentration and a patient`s clinical
response. However these data should be interpreted cautiously
if one is attempting to predict the long-terms relationship
between a carbamazepine dosing regimen and plasma a dosing
interval is some what arbitrary given the long half-life and
relatively short dosing interval, since carbamazepine is slowly
and variably absorbed, the actual sampling time may not be
critical, however, as a general rule, samples should be obtainrd
just before a dose (trough) unless this is markedly inconvenient
for the patient, inconvenience is most likely be encountered in
ambulatory patient who may be taking the drug on a shedule
which is not consistent with their clinic appointments.
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 Equations and Questions:
Question #1:
N.S., a 36-year-old, kg female, is to be given
carbamazepine as an anticonvulsant agent. Calculate a daily dose
that will produce an average steady-state plasma concentration of
approximately 6 mg/1…
To calculate an average steady-state plasma concentration,
equation 16 would be used with an assumed bioavailability of 0.8
and an average clearance value of 3.84 L/hr (0.064 L/kg/hr × 60
kg). The traction of the administered dose which is active drug (s)
is 1.0.
Maitenance Dose =
=
(CL)(Cpssave)(t )
( S )( F )
(3.84 L / hr )(6mg / L)( 24hr / 1day )
(1)(0.8)
= 691.2 mg/day
This dose (approximately 700 mg/day) is that which would be
requested to achieve the steady-state level of 6 mg/L after autoinduction of carbamazepine metabolism had taken place. For this
reason, N.S.should be started on a lower daily dose initially and
increased at one to two week intervals based upon her clinical
response. The usual initial daily dose for adult patients is 200 to
400 mg. With increases of approximately 200 mg every 7 to 14
days.
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Question #2: After two months, N.S.`s carbamazepine dose had
been increased to 300 mg BID. One t this regimen she had some
reduction in seizure frequency, however, seizure control was still
considered unsatisfactory. The steady-state carbamazepine level
at this time was reported to be 4 mg/L. What are possible
explanations for this observed plasma level ? What dose would
be required to achieve a new steady-state carbamazepine level of
6 mg/L ?
Using equestion 35 and a clearance of 3.84 L/hr, the anticipated
carbamazepine level in N.S. for a dose of 600 mg/day would be
approximately 5 mg/L.
Cpss ave =
=
( s )( F )( Dose / t )
Cl
(1)(0.8)(300mg / 12hr )
3.84 L / hr
= 5.2 mg/t.
The observed level of 4.0 mg/L is within the predicted range,
considering the fact that both bioavaibility and clearance values
derived from average literature values may not be applicable to
N.SSSSSSS. At hits point it would be difficult to establish
whether a slightly lower-than-average clearance was responsible
for the observed level of 4.0 mg/t.
Because of carbamazepine`s relatively slow absorption
characteristics and long half-life, it is probable that the measured
concentration of 4 mg/L represents an average value. At steady
state, the average plasma concentration should be proportional to
the daily dose. Therefore, to increase the plasma concentration
from 4 to 6 mg/L, one would simply increase the carbamazepine
dose by 50% (i.e, from 600 to 900 mg/day). An alternate
approach might be to calculate the apparent cabamazepine
clearance for N.S. using equation 15 and an assumed
bioavailability of 0.8.
Cl = ( S )( f )( Dose / t )
Cpssave
15
=
(1)(0.8)(600mg / 24hr )
4mg / L
= 5 L/hr
This clearance value could then be used in equation 16 to
calculate the maintenance dose as illustrated in question 1,
However, this time the clearance value which has been derived
from the patient`s data would be used rather than an average
value from the literature.
Maintenance Dose = (C )(Cpssave)(t )
( S )( F )
=
(5L / hr )(6mg / L)( 24hr / 1day )
(1)(0.8)
= 900 mg/day
If N.S.were receiving other anticonvulsant agents, it would be
appropriate to monitor their concentration as well, since
carbamazepine could include their metabolism, thereby reducing
their steady-state concentrations.
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