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 »  Abstract
 » Introduction
 »  Materials and Me...
 » Results
 » Discussion
 » Conclusion
 » Acknowledgment
 »  References
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Table of Contents    
ORIGINAL ARTICLE
Year : 2015  |  Volume : 63  |  Issue : 2  |  Page : 202-208

Critical appraisal of serum phenytoin variation with patient characteristics in a North Indian population


1 Department of Neuropsychopharmacology, Institute of Human Behaviour and Allied Sciences, Dilshad Garden, Delhi, India
2 Department of Pharmacology and Therapeutics, King George's Medical University, Lucknow, Uttar Pradesh, India
3 Department of Neurochemistry, Institute of Human Behaviour and Allied Sciences, Dilshad Garden, Delhi, India
4 Department of Neurology, Institute of Human Behaviour and Allied Sciences, Dilshad Garden, Delhi, India
5 Senior Research Fellow, Genomics and Molecular Medicine Unit, Institute of Genomics and Integrative Biology, Delhi, India
6 Senior Scientist, Genomics and Molecular Medicine Unit, Institute of Genomics and Integrative Biology, Delhi, India
7 Department of Biostatistics, Institute of Human Behaviour and Allied Sciences, Dilshad Garden, Delhi, India

Date of Web Publication5-May-2015

Correspondence Address:
Dr. Sangeeta Sharma
Department of Neuropsychopharmacology, Institute of Human Behaviour and Allied Sciences, Delhi - 110 095
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0028-3886.156281

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 » Abstract 

Context: Phenytoin (PHT) is one of the frontrunner drugs used as monotherapy in the management of epilepsy. It is also one of the most common drugs causing adverse drug reactions (ADRs). The aim of this study was to study the relationship between serum PHT levels and the age, gender, dosage and genetic polymorphisms in a North Indian population. This knowledge will help in devising drug dosage schedules in various sub-groups of patients as well as in reducing its ADRs.
Materials and Methods: A retrospective analysis of data of 6224 patients from 1998 to 2009 receiving PHT alone for greater than (>) 4 weeks was performed. Patients suspected of being non-compliant, being overdosed or having a hepatic or renal disorder were excluded from the study. Two thousand eight hundred and eighty-eight patients fulfilling the inclusion criteria were divided into three groups: children (1-18 years), adults (19-60 years) and elderly (>60 years).
Results: There was a male preponderance (80%) in all the groups. A significant difference was found in the mean dose between children and adults as well as between children and elderly (P = 0.00). Also, there was a significant difference in the mean concentration and dose ratio between children and adults (P = 0.00). However, a negative correlation was observed between the daily dose and dose ratio (r = -0.36, P = 0.00) that was highest (r = -0.58, P = 0.00) in the elderly. There was a significant gender difference in the mean dose in both children (P = 0.03) and adults (P = 0.00), whereas the mean concentration differed in adults only. Every fifth patient was an intermediate metabolizer (IM) (CYP2C9*1/*3) and showed higher steady state drug levels (>17 mg/L) compared with extensive metabolizers (EMs) (<12 mg/L). The genetic difference between IM and EM was more prevalent in the dose ratio at maintenance dose, with a mean ± SD of 4.041 ± 1.288 mg/L/mg/kg in nine patients carrying the CYP2C9*1/*3 genotype compared with 2.145 ± 0.817 mg/L/mg/kg in 26 patients carrying the CYP2C9*1/*1 genotype (P = 0.00).
Conclusion: North Indian female children and male adults frequently attain a higher serum concentration with the same dose when compared to the other groups. Absence of poor metabolizers may be responsible for a lower number of cases exhibiting toxicity in our population; however, this needs elucidation in a larger number of patients.


Keywords: Drug level, pharmacokinetics, pharmacogenomics, phenytoin, therapeutic drug monitoring


How to cite this article:
Sharma S, Tabassum F, Dwivedi P, Agarwal R, Kushwaha S, Bala K, Grover S, Baghel R, Kukreti R, Tripathi CB. Critical appraisal of serum phenytoin variation with patient characteristics in a North Indian population. Neurol India 2015;63:202-8

How to cite this URL:
Sharma S, Tabassum F, Dwivedi P, Agarwal R, Kushwaha S, Bala K, Grover S, Baghel R, Kukreti R, Tripathi CB. Critical appraisal of serum phenytoin variation with patient characteristics in a North Indian population. Neurol India [serial online] 2015 [cited 2019 Oct 23];63:202-8. Available from: http://www.neurologyindia.com/text.asp?2015/63/2/202/156281



 » Introduction Top


During the past 20 years, better results in the treatment of epilepsy have been obtained through the application of pharmacokinetic data to the pharmacotherapy of epilepsy. Phenytoin (PHT) is one of the commonly used drugs for the management of epilepsy in all age groups. PHT is also one of the most common agents causing adverse drug reactions (ADRs). [1] Monitoring of the PHT serum concentration is a valuable tool in designing a safe and effective therapeutic regimen for epileptic patients. Its serum concentration assessment has been the standard clinical practice to monitor the patient compliance, to evaluate response to therapy and to adjust its dosage. [2],[3]

Although there is an accepted therapeutic range of PHT of 10-20 mg/L, the pharmacokinetics are highly patient-specific and vary in different age groups as multiple factors alter its metabolism and elimination. [4],[5],[6] The dosage adjustment of PHT is complicated because of the non-linear (Michaelis-Menten) pharmacokinetics. [7] As  Michaelis-Menten constant More Details (Km) and the maximum velocity of metabolism (Vmax) depend on the age, weight, sex, race, and the renal and liver functions, the plasma level of PHT is further influenced by these factors. In critically ill patients, the doses of PHT correlate poorly with serum PHT concentrations. [8]

PHT metabolism is predominantly influenced by the CYP2C9 genotype, with minor contributions from the CYP2C19 genotype. Genetic polymorphisms of the CYP2C subfamily are responsible for the great inter-individual variability. [9] A study of CYP2C9 or CYP2C19 polymorphism in healthy individuals was reported from South India, but such studies are lacking in the North Indian population, making it pertinent to study the genetic variability that cause variations in the pharmacokinetic profile. [10] Therefore, the aim of this study was to study the relationship between serum PHT concentration and age, gender, dosage as well as genetic polymorphisms in a North Indian population.


 » Materials and Methods Top


A retrospective analysis of the therapeutic drug monitoring (TDM) data of PHT from the neuropsychopharmacology laboratory was performed for the period from 1998 to 2009. The samples that were included in the study were drawn for assessing the trough PHT levels (sample before the next scheduled dose) in patients receiving PHT alone as an anticonvulsant for more than 4 weeks. The exclusion criteria included samples drawn for evaluating the peak levels; samples from suspected cases of non-compliance or overdose; and, samples from patients with severe renal and/or hepatic disorders.

The total serum drug concentration was measured by an Auto-analyzer from Logitech Pvt. Ltd. (Model Echo) using CEDIA ® PHT II assay kits by Microgenics Corporation, Fremont, USA. Drug levels were categorized into sub-therapeutic (<10 mg/L), therapeutic (10-20 mg/L), supra-therapeutic (20-40 mg/L) and toxic levels (>40 mg/L). All the results in the sub-therapeutic and supra-therapeutic ranges were verified as per the protocol of the quality assurance program. The inter-run and intra-run variation (coefficient of variation) for PHT assay was <10% in the laboratory. A concentration/dose ratio (DR) was calculated for each patient by dividing the steady state concentration (Css; mg/L) by the daily dose (dose; mg/day).

* DR = Css/dose

(* DR or the concentration/dose ratio obtained by dividing the steady state concentration by daily dose)

Patients on PHT monotherapy from our previous pharmacogenomics study were also analyzed for the coexisting genetic polymorphisms in order to understand the correlation of dose with drug levels among the North Indian population. [11] In the pharmacogenetic study, the maintenance dose of a given drug was defined as the dose that had remained unchanged during successive visits in a 12-month period. To obtain the average steady state drug levels at maintenance dose, the mean value of drug level measurements over a period when consecutive doses were documented, was used. Maximum dose of a given drug was defined as the maximum dose a patient had received during the course of the study in the absence of any signs of ADRs. Drug levels at the maximum dose corresponded to a period when the maximum dose was documented.

Genotyping of polymorphisms

A blood sample was collected and the genomic DNA was isolated using a modification of the salting-out procedure. [12] CYP2C9-encoding drug metabolizing enzyme (DME) with functional allele of *2/*3 encoding was selected for the study. Genotypes for two functional polymorphisms {rs1057910 (*2) and rs1799853 (*3)} from the gene were determined by the single nucleotide polymorphism genotyping platform - primer extension reaction followed by MALDI-TOF mass spectrometry (Sequenom Inc., San Diego, CA, USA).

Statistical analysis

The data obtained from the study was statistically analyzed by SPSS (Version 17) using the one-way ANOVA followed by Tukey's test as post hoc analysis. A value of P < 0.05 was considered to be statistically significant. Product-moment correlation coefficient was also calculated to establish the relationship between the PHT level and dose. Genotype frequencies in the study samples were checked for Hardy-Weinberg equilibrium by the χ2 test. Dose, drug levels and dose-adjusted drug levels (dose ratio) were tested between different genotypic categories using the Mann-Whitney U test.


 » Results Top


Of the 6224 drug assays performed in the department, 2888 fulfilled the selection criteria. [Table 1] depicts the patient demographics, and information regarding the breakthrough seizures and adverse events in the different age groups. The distribution according to the various age groups was as follows: children 1220 (42.24%), adult 1638 (56.71%) and elderly 30 (1.03%). There was a male preponderance (approximately 80%) in all the age groups). The mean age (years) ± standard deviation (SD) in children was 13.33 ± 4.16 years, in adults 29.73 ± 9.53 years, and in the elderly 67.37 ± 5.2 years. The breakthrough seizures/relapses (59.6%) and adverse effects (23.1%) were the major reasons for the requests for testing of drug levels in the blood.
Table 1: Patient demographics, breakthrough seizures and adverse events in the different age groups


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[Table 2] depicts the daily dose, concentration, dose ratio and range in the different age groups. A mean dose of 242.71 ± 81.67 mg/day of PHT established the mean blood concentration of 14.51 ± 9.52 mg/L with the mean dose ratio being 0.07 ± 0.06. In children, a mean dose of 207.53 ± 84.68 mg/day established the mean blood concentration of 13.57 ± 9.38 mg/L with the mean dose ratio being 0.07 ± 0.06; whereas in adults, a mean dose of 268.68 ± 68.95 mg/day led to a mean concentration of 15.18 ± 9.57 mg/L with the mean dose ratio being 0.06 ± 0.05. A mean dose of 255 ± 62.08 mg/day in the elderly led to a mean concentration of 16.01 ± 9.32 mg/L with the mean dose ratio being 0.07 ± 0.06. Although the mean dose was highest in the adults (268.68 mg/day), the mean drug concentration (16.01 mg/L) was highest among the elderly patients. The mean dose administered (268.68 mg/day) in adults was probably less than the optimal dose, resulting in a high percentage of requests for estimation of drug levels due to the presence of breakthrough seizures (that occurred in 57.3% patients) in this group [Table 1].
Table 2: Daily dose, concentration dose ratio and range in the different age groups


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A sub-therapeutic serum PHT level was found in 42.6% of children, 33.3% of adults and 10% of the elderly, whereas PHT levels in the supra-therapeutic range were found in 15.7% of children, 21.1% of adults and 30% of elderly patients. In all the three age groups, about 40% levels were within the therapeutic range; however, in approximately 2.6% children and adults, the PHT concentrations were found to be in the toxic range. The drug levels in the supra-therapeutic range were matched for adverse effects [Table 2]. Only 38% of the cases were in the sub-therapeutic range, although the breakthrough seizure/relapse rate was 60%, suggesting that a high probability of sub-optimal dosing existed, and also that break-through seizures may have occurred even in the supra-therapeutic/toxic range of the medication [Table 1].

There was a significant difference in the mean dose between the children and adults and also between the children and the elderly (P = 0.00). There was a significant difference in the mean concentration and dose ratio between the children and adults (P = 0.00) [Table 3]. With the least mean dose, the dose ratio was highest in children, even more so in female children.
Table 3: Comparison among different age groups of daily dose, concentration and dose ratio


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A negative correlation was observed between the daily dose and dose ratio (Pearson correlation coefficients r = -0.36, P value = 0.00) for the entire set of study subjects, and it was highest (r = -0.58, P value = 0.00) in the elderly patients. The dose and concentration level were positively and moderately correlated in all the three age groups, but had maximum magnitude of correlation in children (r = 0.31, P value = 0.00) [Table 4].
Table 4: Correlations between age, dose, concentration and dose ratio in the different age groups


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There was a significant gender difference in the mean doses in children (P = 0.03) and in adults (P = 0.00), but the mean concentration difference between the genders was significant in adults only. There was no gender difference for the dose ratio in the adults and the elderly, but the gender difference for the dose ratio was of borderline significance in children (P = 0.05) [Table 2] and [Table 5]. The mean dose ratio was the highest in female children (0.08 ± 0.07), showing a similar PHT concentration in blood even with a lesser dosing (197.30 ± 82.19 mg/day) compared with the male children. In adults, lesser dosing in the female patients led to a lesser blood concentration compared to that of the male subjects in the group.
Table 5: Gender differences in the different age groups


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In a subset of patients enrolled in our previous pharmacogenomics study, it was observed that one out of every five patients suffering from epilepsy was an intermediate metabolizer (IM) (harboring the CYP2C9*1/*3 genotype) of PHT. The IMs showed significantly higher steady state drug levels (>17 mg/L) as compared with extensive metabolizers (EMs) (<12 mg/L) [Table 6]. The genetic difference between the two groups of patients was more prevalent in the dose-adjusted drug levels (dose ratio) at maintenance dose, with a mean of 4.041 ± 1.288 mg/L/mg/kg in nine patients carrying the CYP2C9*1/*3 genotype compared with a mean of 2.145 ± 0.817 mg/L/mg/kg in 26 patients carrying the CYP2C9*1/*1 genotype (P values = 0.00016).
Table 6: Association analysis of genetic variants from CYP2C9 with dosing and drug levels of PHT


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 » Discussion Top


The present study was conducted to understand the effects of age, gender, dose and dose ratio on the serum PHT concentration in the different age groups in the North Indian population. It also attempted to study and correlate the far-reaching consequences of genetic polymorphisms in the North Indian population on serum PHT concentration.

In all age groups, the mean dose was frequently on the lower side of the recommended daily dose of 300 mg/day, but the mean serum concentration was well within the therapeutic range of 10-20 mg/L. [7],[13] Mawer et al. calculated a PHT sodium mean dose of 345-400 mg/day as being required to attain steady state serum concentrations of 10-20 mg/L. [6] In our study, the steady state mean serum concentration was within the therapeutic range despite the lesser dosing probably due to either its slower metabolism or its lesser clearance in the North Indian population under study.

The mean concentration was the highest among the elderly despite a lesser mean dosing than in adults. A similar result was found by Wright and Begg in 2010, suggesting the presence of a reduced free PHT "apparent clearance" in the elderly, although statistically significant results were not found. [14] This is probably due to their decreased metabolism and clearance when compared with adults; or, due to a better compliance among the elderly. On the contrary, Sirmagul et al. found no significant difference between the average plasma concentrations of PHT among the age groups. [15]

In the present study, a significant but weak positive correlation was found between the daily dose of PHT and its plasma concentration in the children and adult groups, and the correlation was the strongest in children. The dose ratio was negatively correlated with the daily dosage in all age groups (which means that when the daily dosage was increased, the dose ratio decreased; or, its metabolism and excretion, or its clearance, increased). The strongest negative correlation occurred in the elderly. Similar results were obtained by Hayes et al. who stated that PHT clearance showed a marked increase in people over 65 years of age compared with people under it, probably due to the decreased concentration of plasma proteins as well as decreased PHT-protein binding. [5]

In the present study, gender difference in the mean dose in all the groups was observed, but it was only significant in children. The female patients in each group attained the therapeutic range concentration in plasma with a mean daily dose that was 10% less than the mean daily dose of the male patients. However, the serum concentration achieved in the respective age groups reached a significant level only in adult male and female patients. Similar results were observed in the study by Sirmagul et al., where the plasma PHT concentration was reported to be higher in female patients. [15] However, opposite results were reported by Houghton et al. and others, who stated that gender did not play a significant role in PHT-protein binding or on the plasma PHT levels. [15],[16],[17],[18],[19] With a lower mean dose in females, the dose ratio was the highest among female children. The increased dose ratio could be due to a variety of reasons, such as increased bioavailability (absorption and transport across cells), increased plasma protein binding and increased albumin level or due to decreased metabolism and clearance. On the contrary, clearance was the highest among children because of the highest Vmax existing in them. [20]

In the present study, the maximum number of cases fell in the therapeutic range (41.3%), followed by the sub-therapeutic range (37.2%) and the supra-therapeutic range (18.9%), and only 2% of the cases were in the toxic range. The high proportion of patients lying in the supra-therapeutic range is in conformance with the frequency of altered metabolizer phenotype (CYP2C9*1/*3) observed in 22% of patients in our pharmacogenomics study. Furthermore, absence of poor metabolizers (patients showing CYP2C9*2/*2 or CYP2C9*3/*3 or CYP2C9*2/*3) may be responsible for less number of toxic cases in our population compared with other developing and developed countries. In the developing countries, the TDM pattern of PHT was found to be sub-therapeutic in 32%, therapeutic in 51% and toxic in 17% subjects whereas in developed countries, the TDM pattern of PTH was found to be sub-therapeutic in 48%, therapeutic in 32% and toxic levels in 20% of them. [21] The therapeutic drug monitoring pattern reported in our set up was resembling that observed in other developing countries.

Two inter-related factors are clearly important in determining the serum concentration of PHT produced by a given dose of the drug. Genetic variations of multifactorial type are considered to be responsible for differences in the rate of metabolism of PHT from one patient to another, but this influence is greatly magnified by PHT inhibiting its own metabolism. Genetic factors presumably determine a patient's basic endowment of hydroxylase enzyme, its capacity to hydroxylate and its sensitivity to substrate inhibition. The prevailing steady state serum PHT concentration, however, determines the actual proportion of the drug that is metabolized by the liver enzymes. The interaction between these factors can lead to marked differences in the dose/serum concentration relationship between subjects.

Limitations

Due to the limitations imposed by a retrospective study design and the patient groups recruited for the study being registered in only one hospital, the results may not be applicable to the general population. Another drawback was that only those cases, in whom estimation of the drug level was being requested, were included in the study. A relatively smaller number of cases in the elderly age group (reflecting the prescribing pattern of the medication, or the difficulties encountered by the elderly in accessing the available hospital facilities); and, of those inducted in the genetic polymorphism study, are the other major limitations.


 » Conclusion Top


All medical advancements have the ultimate purpose of optimizing patient care and beneficence. The therapeutic drug monitoring of anticonvulsants contributes in this respect by facilitating titration of the dosage of anti-epileptic drugs to prevent their unwanted effects and to avoid their empiric administration. The present study highlights the differences in dosage and blood levels in various age groups and genders. Thus, dose reduction is needed in the elderly and in female patients, especially in female children. A negative correlation of dose ratio with the daily dosage is another difference that needs further elaboration in the larger population. Ours is the population that probably needs a lower dosage of PHT when compared with the standard dosage recommended for Caucasians to achieve a similar plasma PHT level. Whether or not this lower dosage actually leads to a suboptimal response in majority of our population; and, is genetic variation in 2C9/2C19 also contributing to the response to PHT, and to the prevailing serum levels of PHT, are questions that need elucidation in a larger population.


 » Acknowledgment Top


The authors would like to thank Mrs. Vinita for data entry and all the patients who were part of this study.

 
 » References Top

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Grover S, Gourie-Devi M, Bala K, Sharma S, Kukreti R. Genetic association analysis of transporters identifies ABCC2 loci for seizure control in women with epilepsy on first-line antiepileptic drugs. Pharmacogenet Genomics 2012;22:447-65.  Back to cited text no. 11
    
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Sirmagul B, Atli O, Ilgin S. The effect of combination therapy on the plasma concentrations of traditional antiepileptics: A retrospective study. Hum Exp Toxicol 2012;31:971-80.  Back to cited text no. 15
    
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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]



 

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