A Preliminary Report Of Therapeutic Drug Monitoring Of Antiepileptic Drugs

The present study was under taken to analyze the data of serum concentration
of four commonly used antiepileptic drugs in referred patients with an idea
to assess its utility to the physician in the management of patients with epilepsy.
A total of 95patients, of both genders and aged between 7-50 years, were analyzed.
Plasma levels of the drugs were measured by homogeneous enzyme immunoassay using
semiautomatic analyzer (Erba Chem Pro).The results of the present study establishes
the relationship between drug concentration and biological effects. In the present
study 20% of all the patients (60% on phenytoin and 25% on phenobarbitone) had
sub-therapeutic levels. These patients required dosage increments for
better control of seizures. Majority of the patients (50%) had serum levels
within the therapeutic range. 27.5% patients (31% on CBZ, 8.8% on phenytoin,
50% on valproic acid and 31.2% on phenobarbitone) had toxic levels and
required dosage reduction. Non-compliance was observed in 1.7% patients
where no detectable blood levels were observed. Hence, indicating that evaluation
of serum levels of antiepileptic drugs can be of immense help in clinical management
of patients with epilepsy by revealing under or over dosage and detecting failure
of compliance.

Key Words; Therapeutic, Drug, Monitoring, Antiepileptic

Introduction:

Pharmacokinetic variability is one of the major factors responsible for the
inter-individual and intra-individual variation in response to drugs. For limited
number of drugs measuring the clinical response (example blood pressure) is
easy and can be used to individualize the drug therapy. However, for most of
the drugs measurement of clinical response is not possible, for these drugs
measurement of plasma drug concentration can be usefully applied to individualize
dosage to improve the overall outcome. Measurement of plasma concentration of
antiepileptic drugs (AED) is necessary to enhance the efficacy of therapy as
the therapeutic response cannot be immediately measured and signs of toxicity
cannot be easily recognized on purely clinical grounds. In addition many antiepileptic
drugs have a narrow therapeutic range¹.

Carbamazepine ²(CBZ) is an anticonvulsant drug used for the treatment of partial seizure, grandmal epilepsy and trigeminal neuralgia. Effective serum concentration of CBZ is important for seizure control. However, serum CBZ concentrations show only a moderate correlation to administered dose, due to individual differences in absorption, metabolism and clearance. It has a narrow therapeutic index and induces its own metabolism. Co-administration of another antiepileptic drug like phenytoin or phenobarbitone can significantly alter serum CBZ levels.

Phenytoin ³(DHP) is one of the most widely prescribed anti-convulsant drugs for the treatment of epilepsy, particularly grandmal, cortical focal seizure and temporal lobe epilepsy. Monitoring phenytoin concentration is essential during therapy as it has saturable kinetics, narrow therapeutic index and wide variability in individual rate of drug absorption, metabolism and excretion.

Valproic acid ⁴(VPA) is currently used to treat various seizure disorders, to prevent migraine and in substance abuse withdrawal. It is an interesting drug from pharmacokinetic point of view as it influences the metabolism of a number of other anticonvulsant drugs like phenytoin and phenobarbitone. Monitoring serum levels of valproic acid are important in children, in patients of liver and renal disease and in pregnant females.

Phenobarbitone ²(PB) is a long acting barbiturate, used in the treatment of seizures. Monitoring its levels is important in pregnancy, hepatic disorder and when other anticonvulsants such as valproic acid or phenytoin are co administered with it.

In this study an attempt has been made to analyze the data of serum concentration
of four commonly used antiepileptic drugs in referred patients with an idea
to assess its utility to the physician in the management of patients with epilepsy. 

{mospagebreak title=Materials and Methods}

Materials and Methods

The present study is a three-month retrospective analysis of plasma concentrations of phenytoin, carbamazepine, valproic acid and phenobarbitone in patients of epilepsy. A total of 95patients, of both genders and aged between 7-50 years, were analyzed. These patients were referred from the departments of Pediatrics, Internal Medicine and Psychiatry to the therapeutic drug-monitoring center in the department of Pharmacology & Therapeutics, Government medical collage, Jammu (India). All the patients had taken the drug for a minimum of 30 days to measure the steady state levels. Blood samples were obtained just before the next scheduled dose to record the trough levels. Plasma levels of the drugs were measured by homogeneous enzyme immunoassay using semiautomatic analyzer (Erba Chem Pro). Lowest detectable concentration with this technique is 0.5µg/ml.

{mospagebreak title=Results}

Results:

(Table: 2, 3)Total of 95 patients (39 on CBZ, 29on DHP, 10 on valproic acid
and 17 on phenobarbitone) were analyzed. Normal range of sub therapeutic, therapeutic
and toxic concentration of these drugs is given in table 1. These patients were
put into four groups- CBZ, DHP, VPA and PB. They were further categorized into
four categories depending on their plasma drug concentrations- not detectable,
sub-therapeutic, therapeutic and toxic.

Results of the study showed that out of 39 patients on CBZ, 26 patients had
serum levels in therapeutic range. Toxic levels were detected in 12 patients
and 1 patient had no detectable levels of drug in the serum. None of the patients
in this group had sub-therapeutic levels. Out of 29 patients on phenytoin,16
patients had sub-therapeutic levels, 11 patients had therapeutic levels and
2 patients showed toxic levels. 5 patients on valproic acid out of total of
10 had serum levels within therapeutic range and 5 patients had serum levels
corresponding to toxic levels. No patient on valproic acid had sub-therapeutic
levels. Among 17 referred patients on phenobarbitone, 4 showed sub-therapeutic
levels, 6 therapeutic levels, 5 toxic levels and 2 patients had no detectable
drug levels in the serum. Most of the requests were for CBZ followed by DHP,
PB and VPA. Overall out of investigated 95 patients for TDM, 20(19.5%) patients
had sub-therapeutic levels, 48 patients (50.5%) had therapeutic levels and 24
patients (27.5%) had toxic levels. In only 3 patients (2.2%) no drug levels
were detected suggesting non-compliance. Steady state plasma concentrations
in 95 patients on CBZ, DHP, VPA and PB were within the range of 6.18μg/ml-16.71μg/ml,
4.9μg/ml-36μg/ml, 21.2μg/ml-167μg/ml and 10μg/ml-89.99μg/ml
respectively.

Table 1: Therapeutic, sub-therapeutic and toxic levels of CBZ, DHP, VPA
and PB

Table2: Distribution of patients with reference to their plasma drug levels.

 Table3: Steady sate plasma concentration.

{mospagebreak title=Discussion}

Discussion

Evaluation of serum levels of antiepileptic drugs have been shown to have immense
help in clinical management of patients with epilepsy by revealing under or
over dosage and detecting failure of compliance⁵.The results of our
study also reasonably establishes the relationship between drug concentration
and biological effects. In the present study 20% of all the patients (60% on
phenytoin and 25% on phenobarbitone) had sub-therapeutic levels. These patients
required dosage increments for better control of seizures. Majority of the patients
(50%) had serum levels within the therapeutic range. 27.5% patients (31% on
CBZ, 8.8% on phenytoin, 50% on valproic acid and 31.2% on phenobarbitone) had
toxic levels and required dosage reduction. Non-compliance was observed in 1.7%
patients where no detectable blood levels were observed. This underscores the
utility of TDM in patients not showing desired control of seizures in spite
of adequate medication. Wide range of fluctuation in the steady state concentration
of the four-anticonvulsant drugs was noted in our study that further emphasizes
the need of individualization of AED therapy by measuring plasma drug concentrations.

Similar pattern of antiepileptic drug serum levels have been reported by Garg et al⁶, who analysed the TDM data of two antiepileptic drugs- phenytoin and carbamazepine. They have also shown that therapeutic levels were achieved in greater number of patients on CBZ (75.6%) as compared to 32.8% of patients on phenytoin. Such differences were ascribed to complex pharmacokinetic behavior of pheytoin in terms of saturable kinetics and unpredictable bioavailability.

Irshad et al⁷ evaluated the results of plasma concentration of antiepileptic drugs. They found that most of the requests for TDM were for phenytoin followed by CBZ, VPA and PB. This is in contrast to our study were maximum requests were made for CBZ and least for VPA. This discrepancy could be due to difference in the prescribing pattern of physicians in our institution compared to theirs. They also showed that majority of patients on PB had serum levels within the therapeutic range followed by CBZ, VPA and DPT while our study reports that most of the patients on CBZ therapy had serum levels within therapeutic range followed by PB, VPA and DPT.

Kokwaro et al⁸ measured the steady state plasma levels of AED in 15 patients of epilepsy. They reported wide fluctuation in steady state levels similar to our results. They also detected non-compliance in 26.6% of patients, which is much higher compared with our results. However their sample size was too small to draw any definite conclusion.  

The results of present study suggest the importance of routine monitoring of the levels of antiepileptic drugs in patients with seizures. Detection of non-compliance, toxicity and failure of adequate response because of sub-therapeutic drug levels emphasize the utility of therapeutic drug monitoring of antiepileptic in patients with seizures. Clinical response aided with plasma monitoring of these drugs will help to improve effectiveness and safety of these drugs. Although the pattern of plasma drug levels observed in this study might be different than those observed in general epileptic population as only those patients with poor seizure control or toxic symptoms are referred for TDM. We conclude that routine monitoring of antiepileptic drug levels may help the clinician to improve the over all out come of the patients in terms of reduced adverse events and better seizure control.

Follow up action was advised in most of the patients. In patients with sub-therapeutic
levels, increase in the dose of antiepileptic drug was advised. Similarly in
patients with toxic levels reduction the dose of drug was advised. In patients
with poor seizure control but serum levels of the drug within the therapeutic
range, addition of another antiepileptic drug was advised. Non-compliance as
a cause of treatment failure was detected in 3 patients.

{mospagebreak title=References}

References:

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3.Tokola RA, Neunen PJ. Pharmacokinetics of antiepileptic drugs. Acta Neurol
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4.Gugler R, Von Unruh GE. Clinical pharmacokinetics of valproic acid. Clin
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5.Yukawa. E. Optimisation of antiepileptic therapy.
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{mospagebreak title=About Authors}

Authors :

Dr Vishal. R. Tandon*, Dr D. Kour , Dr B. Kapoor , Dr V. Khajuria ,
Dr B.M. Gupta
Post Graduate Department of Pharmacology & Therapeutics, Govt Medical College,
Jammu (J&K) India – 180001,

* Author for correspondance

Dr Vishal R.Tandon has received his doctorate in Pharmacology
from Nagpur University, Maharashtra (India) in Dec, 2002.He has authored and/or
coauthored over 50 publications in many national and international journals.
Two chapters in different national books are also to his credit. His research
interests include herbal drug screening, especially working on plant Vitex negundo.
He is Expertise in designing and conducting clinical trials. He is currently
working as Senior Demonstrator Post graduate department of pharmacology and
therapeutics, GMC, Jammu (J&K)-India. His current job responsibilities include
teaching UG/PG classes as well as supervising research. He bears following post,
a) Editorial Secretary JK-SCIENCE,
Journal of Medical Education & Research . This Journal is indexed in Excerpta
Medica/EMBASE, Ulrich periodical Dictionary& Indian Science Abstract. b)
Secretary-Indian Rheumatology Association-J&K CHAPTER. c) Pear reviewer
World Journal of Medical Science. He is also life Member of Indian
Pharmacological society, Association of Physiologist and Pharmacologist
of India, Indian
Rheumatology Association and Indian Menopause Society.

Contact info: Dr Vishal. R. Tandon(Senior Demonstrator)
(MD), Post Graduate Department of Pharmacology & Therapeutics, GMC, Jammu
(J&K) India - 180001. E-mail:dr_vishaltandon@yahoo.com, Phone: 9419195126

Dr D. Kour is currently working as Senior Demonstrator in the Post graduate Department of Pharmacology and Therapeutics, GMC, Jammu (J&K)-India.

Dr B. Kapoor (Professor& Head), Post graduate Department of Pharmacology
and Therapeutics, GMC, Jammu (J&K)-India is a well known personality in
field of Pharmacology in India. He has many publications to his credit and is
key person responsible for up-lifting the Department of Pharmacology, GMC, Jammu
in militancy affected state Jammu and Kashmir.

Dr V. Khajuria is currently working as Lecturer in Post graduate Department of Pharmacology and Therapeutics, GMC, Jammu (J&K)-India.

Dr B.M. Gupta  is currently working as Lecturer in Post
graduate Department of Pharmacology and Therapeutics, GMC, Jammu (J&K)-India.