Therapeutic Drug Monitoring of Carbamazepine
Dipesh Raj Panday1*, Karishma Rajbhandari Panday2, Madhur Basnet3, Shyam Kafle4, Bhupendra Shah5and GP Rauniar1
1Department of Clinical Pharmacology and Therapeutics, BP Koirala Institute of Health Sciences (BPKIHS), Nepal
2Department of Basic and Clinical Physiology, BP Koirala Institute of Health Sciences (BPKIHS), Nepal
3Department of Psychiatry, BP Koirala Institute of Health Sciences (BPKIHS), Nepal
4Department of Pediatrics and Adolescents Medicine, BP Koirala Institute of Health Sciences (BPKIHS), Nepal
5Department of Internal Medicine, BP Koirala Institute of Health Sciences (BPKIHS), Nepal
- *Corresponding Author:
- Dipesh Raj Panday
Assistant Professor, Department of Clinical Pharmacology and Therapeutics
BP Koirala Institute of Health Sciences
Tel: + 9779862124700
E-mail: [email protected]
Received date: February 02, 2017; Accepted date: February 11, 2017; Published date: February 18, 2017
Citation: Panday DR, Panday KR, Basnet M, Kafle S, Shah B, et al. (2017) Therapeutic Drug Monitoring of Carbamazepine. Int J
Neurorehabilitation Eng 4:245. doi:10.4172/2376-0281.1000245
Copyright: © 2016 Panday DR, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted
use, distribution, and reproduction in any medium, provided the original author and source are credited.
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Carbamazepine is one of the classical antiepileptic drugs, chemically related to the Tricyclic Antidepressants. There are different methods to detect Carbamazepine in plasma i.e. Therapeutic Drug monitoring (TDM). Various studies claim the usefulness of TDM of Carbamazepine but clear-cut guidelines for TDM are still lacking. This article is authors’ endeavour to summarize facts in different publications on TDM of Carbamazepine. Electronic databases MEDLINE/PubMed, Google Scholar, IMSEAR (Index Medicus for South-East Asia Region) and Scopemed were extensively searched with Mesh (Medical Subject Headings) terms “Carbamazepine” AND “drug monitoring” from earliest possible date (1966) to December, 2016. Articles in any language especially those published in recent years were given preference. For non-English articles, Google translation was used and only abstracts were included. Review is mostly centred on toxic effects, poorly adjusted therapies and poor seizure control. Individualization of drug dose with the help of plasma level detection is a must in case of Carbamazepine therapy. TDM helps better outcome by minimizing the risk of under or overdosing due to drug/food interaction or genetic polymorphism of enzymes and transporters involved in the metabolism of Carbamazepine.
Anticonvulsants; Carbamazepine; Drug monitoring;
Epilepsy; High pressure liquidchromatography.
Carbamazepine is an antiepileptic drug, chemically related to the
Tricyclic Antidepressants. It is an iminostilbene-derivative with a
carbamyl moiety at the 5th position of the molecule. This moiety is
essential for its anti-seizure activity .
High-performance liquid chromatography (HPLC) with diode array
detector, gas chromatography mass spectrometry, etc. . are few
methods to detect Carbamazepine in plasma. HPLC is a simple,
sensitive, accurate and cost-effective method [3,4] and it gives high
recovery with exact precision .
There are also other methods to detect Carbamazepine in plasma.
Some of them are:
Micellar electrokinetic capillary chromatography 
Microextraction by packed sorbent method 
Fluorescence polarization assays 
Many reports claim the usefulness of TDM of Carbamazepine but
clear-cut guidelines for TDM are still lacking. This article is authors’
endeavor to summarize facts in different publications on TDM of
Electronic databases MEDLINE/PubMed, Google Scholar, IMSEAR
(Index Medicus for South-East Asia Region) and Scopemed were
extensively searched with Mesh (Medical Subject Headings) terms
“Carbamazepine” AND “drug monitoring” from earliest possible date
(1965) to December, 2016. Articles in any language especially those
published in recent years were given preference. For articles published
in non-English, only abstracts were reviewed.
Metabolism and interaction
Carbamazepine plasma level is affected by several factors . It is
altered by age and pregnancy status including several other factors
Carbamazepine is primarily metabolized by Cytochrome P4503A4
in the liver. Its major metabolite is Carbamazepine-10,11-epoxide,
which also retains anti-epileptic and toxic property. RoutineTDM of
Carbamazepine-10,11-epoxide is not considered necessary. However, it
might be beneficial in patients taking Carbamazepine with other antiepileptic
drugs susceptible to pharmacokinetic interaction, in
suspected toxicity and renal insufficiency [11-14].
Again, Carbamazepineis a potent inducer of its metabolizer,
Cytochrome P4503A4, i.e., it is an auto-inducer. Therefore, there is
significant decrease in plasma drug levels during the first few weeks
due to auto-induction [15,16]. Hence, timing of TDM is very
important in case of Carbamazepine because there is significant decrease in plasma drug levels during the first few weeks due to autoinduction
After some time, with a single extended-release dose of
Carbamazepine, the average half-life range from 35-40 h .
The free fraction Carbamazepine shows considerable interindividual
variability, especially in the presence of associated disease or
drug interactions and multiplicity of variables . Aberrantly low
plasma levels are more likely due to surreptitious noncompliance or
drug interactions with enzyme inducers .
Being a potent Cytochrome P4503A4 inducer, it also decreases the
plasma concentration of many psychotropic, immunosuppressant,
antineoplastic, antimicrobial, and cardiovascular drugs, as well as oral
contraceptive steroids which are metabolized by the same cytochrome
isoform. On the otherhand, certain macrolide antibiotics, azole
antifungals and isoniazid inhibit this isoform, thereby, enhancing its
plasma half-life and serum concentration [20,21].
As anticipated, Fluvoxamine, inhibitor of CYP4503A4, significantly
increases plasma levels of Carbamazepine . However, fluoxetine,
primarily metabolized by CYP2D6, does not interact with
Carbamazepine . Similarly, pomegranate juice, which inhibits
cytochrome P4503A4, significantly increases the AUC of orally
administered Carbamazepine in rats .
Interaction with anti-epileptics
Plasma concentration of Carbamazepine is significantly lower in
polytherapy than in monotherapy . Vigabatrin decreases plasma
concentration of Carbamazepine by increasing its clearance not
catabolism . Topiramate interferes Carbamazepine plasma level
. Zonisamide may increase its serum levels of Carbamazepine in
some patients  and not alter the level of Carbamazepine or
Carbamazepine-10,11-epoxide in other . Topiramide Clearance
was 70% higher in patients co-treated with Carbamazepine and was
found to increase with patient age .
However, all interaction is not pharmacokinetic. Carbamazepine
plus Stiripentol (a newer anticonvulsant) interact pharmaco
dynamically and the benefits may outweigh the usual disadvantages of
Interaction with CNS drugs
Haloperidol increases the serum Carbamazepine level  but
Carbamazepine decreases the concentration of Haloperidol by 37%
When Carbamazepine was co-administered with quetiapine, the
clearance of quetiapine was significantly higher (p=0.01) [34-36].
Carbamazepine comedication with Pregabalin, can moderately
decrease Pregabalin serum concentrations by about 20% to 30% .
Patients co-medicated with Carbamazepine had a 71% lower
median concentration/dose (C/D) ratio for Olanzapine than patients
on Olanzapine monotherapy .
Comedication with the CYP3A4 inducer Carbamazepine lowered
the dose-adjusted aripiprazole concentration by 88% .
Carbamazepine decreases Methadone blood concentrations,
probably by induction of CYP3A4 activity, which can result in severe
withdrawal symptoms . The mean C/D of both Amitriptyline and Nortriptyline in patients
on Carbamazepine was about 50% lower than in those treated with the
antidepressant only .
Interaction with cardiovascular drug
Amlodipine decreases the metabolism of Carbamazepine .
Similarly, a potentially harmful drug-drug interaction may occur if
Carbamazepine and Diltiazem or Verapamil are administered
concurrently [43,44]. Some of these interactions may have potential
implication for pharmacological basis of rational polytherapy.
Similarly, Flunarizine Nicardipine distinctly increases the level of
Carbamazepine in plasma . On the other hand, Caffeine
diminishes the efficacy of Carbamazepine .
Uses and advantages of carbamazepine
Carbamazepine has been successfully employed in a variety of
neurological and psychiatric disorders . Carbamazepine
monotherapy is one of the most frequently prescribed antiepileptic
drug therapy . It is the drug of choice (DOC) or first line drug for
partial seizures and most grand mal seizure [47-49]. It even shows
usefulness in refractory partial epilepsy . It has also been tried in
alcohol withdrawal seizures [51,52]. It is specially preferred for not
being problematic in terms of weight gain and adverse metabolic
concerns . Moreover, it is a preferred antiepileptic for those with
intellectual disability, balance disturbances and cognitive dysfunction
. Together with ethosuximide, it is used to treat epileptic mixedseizure
patterns . It also has mood-stabilizing and anti-maniac
effect. The antimanic response is significantly correlated with the
plasma levels of both Carbamazepine and its epoxide metabolite .
One preliminary study shows that Carbamazepine may be an effective
anticonvulsant for neonatal seizures . Carbamazepine is one of the
time-tested drugs of Trigeminal Neuralgia [58,59].
Importance of TDM
Carbamazepine plasma level is directly correlated with dose,
therapeutic effect and side effects [50,60,61]. A study revealed that with
Carbamazepine, there is non-linear relationship between the dose and
the plasma concentration even within the range of therapeutic doses
. Normally for any drug, TDM (measurement of serum drug
concentrations) is meaningful in three conditions.
1. When drug interactions are expected
2. When toxicity suspected
3. When drugs have nonlinear pharmacokinetics .
Many times pharmacodynamic resistance rather than
pharmacokinetic, is responsible for lack of efficacy of Carbamazepine
in non-responding epileptic patients . This is revealed by serum
plasma level of the drug. At times plasma level of Carbamazepine helps
us to rule out toxicity from idiosyncratic reaction like Carbamazepine
Efficiency of learning new information and memory-scanning rate
displays a concentration-dependent relationship with Carbamazepine
level, with poor performance significantly associated with its higher
plasma concentrations therefore plasma level monitoring may help
prevent unnecessary concentration dependent cognitive decline by
keeping plasma level at the lower therapeutic range [66,67].
Carbamazepine elimination is related to genetic polymorphisms of
drug metabolizing enzymes and transporters. It adds another reason for plasma monitoring and individualization as the drug level may
become unpredictable in them . Literature says once seizures are
controlled, plasma levels of the drug should be measured to establish
optimum levels for individual patients being treated. Most studies
emphasize the importance of early diagnosis of the condition and early
treatment aided with frequent plasma level monitoring [69,70].
Recommended plasma level of carbamazepine
Therapeutic range of Carbamazepine in plasma is 5 to 10 μg/ml
; more specifically, 7.4 μg/ml for adults and 8.2 μg/ml for children
. In bipolar patients, mean values of Brief Psychiatric Rating Scale
(BPRS) scores were better when plasma Carbamazepine
concentrations was 7 μg/mL . Literature shows during Plasma drug
level monitoring, trough levels, should provisionally be aimed at
between 6 to 8 μg/mL and in order to avoid toxic effects, peak levels
should not exceed 12 or even 10 μg/mL .
In a study done in Patan Hospital, Nepal, Carbamazepine level was
tested in 241 patients and it was found that 79.3% of them had at
therapeutic drug level, 15.8% had sub therapeutic drug level and 4.9%
had toxic level. Study concluded that monitoring of Carbamazepine is
helpful when their toxicity and efficacy are doubtful .
In an Indian study, 15 out of 25 on Carbamazepine had plasma
levels within the therapeutic range .
Features of toxicity
There is a correlation between plasma free Carbamazepine levels
and manifestations of toxicity . Acute intoxication causes
neurologic and cardiovascular dysfunction. Neurologic manifestations
may range from mild ataxia to profound coma with respiratory failure.
Cardiovascular effects appear primarily as conduction system
disturbances . Coma, somnolence, cerebellar syndrome and
epileptic seizures are often seen in its overdose survivors . Blood
Levels of alkaline phosphatase were significantly more in patients
compared to controls . Carbamazepine plasma level
determinations can at times provide explanation for toxicity . Few
anti-epileptics like Carbamazepine meet the theoretical criteria
justifying free drug level monitoring .
Carbamazepine and pregnancy
Carbamazepine is FDA pregnancy category D drug. However, it is
considered that the teratogenicity of Carbamazepine is significantly
lower than other classical antiepileptics . Therefore, during
pregnancy, it is one of the most preferred anticonvulsant. However,
altered body physiology during pregnancy remarkably twists its
metabolism [10,81]. Total Carbamazepine concentration is slightly
lower during the third trimester as compared with baseline, whereas
free concentration is unchanged .
Alternative to plasma for carbamazepine level detection
Various studies suggest a possibility of using saliva as an alternative
biological material for determination of Carbamazepine
concentrations in therapeutic application as well as in acute poisoning
and a possible extrapolation of the results obtained in saliva to serum
concentrations of Carbamazepine [82-85]. Again although it had been
suggested by several authors that the measurement of Carbamazepine
in hair might provide a better index of individual dosage history than
the plasma level assays, the deviations observed in the study led by Kintz et al.  concluded that hair samples are not suitable for
evaluating the quantity of drug consumed. The Carbamazepine
concentration in breast milk ranged from 0.34-0.86 mg/L .
Individualization of drug dose with the help of Plasma level
detection is a must in case of Carbamazepine therapy. It helps to
minimize the risk of under or overdosing due to drug/food interaction
or genetic polymorphism of enzymes and transporters involved in the
metabolism of Carbamazepine.
Authors will like to acknowledge Professor Dr. Bishnu Hari Paudel
for going through the manuscript and giving his expert opinion on the
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