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ORIGINAL ARTICLE
Year : 2012  |  Volume : 60  |  Issue : 2  |  Page : 146--149

An initial experience with therapeutic drug monitoring of levetiracetam as reported from a pediatric clinical setting in India

BS Mathew1, DH Fleming1, M Thomas2, R Prabha1, K Saravanakumar1,  
1 Department of Pharmacology and Clinical Pharmacology, Christian Medical College, Vellore, Tamil Nadu, India
2 Department of Neurology, Christian Medical College, Vellore, Tamil Nadu, India

Correspondence Address:
B S Mathew
Clinical Pharmacology Unit, Department of Pharmacology and Clinical Pharmacology, Christian Medical College Hospital, Vellore-632004, Tamil Nadu
India

Abstract

Background and Objectives: Monitoring of levetiracetam in routine clinical practice is not strongly recommended. The aim of this study was to investigate any difference in serum levetiracetam concentration between patients on enzyme-inducing and -inhibiting antiepileptic co-medication and also to identify any correlation between levetiracetam concentration and clinical response. Materials and Methods: This study included pediatric patients with epilepsy from a tertiary care referral hospital in India. Details of antiepileptic co-medication, seizure frequency before and after initiating levetiracetam were recorded. Serum trough levetiracetam concentration was measured. Results: Of the 69 children recruited in the study, 55 children had >50% reduction in seizure frequency compared to baseline seizure frequency. Eight patients showed no improvement. The serum concentration of levetiracetam was more than 10 μg/ml in 78.2% of responders and 75% non-responders. There was no difference in dosing between responders and non-responders. Patients on enzyme-inducing co-medication had lower median serum levetiracetam concentrations (7.3 μg/ml) compared to those on enzyme-inhibiting co-medication (14.4 μg/ml) or those without interfering antiepileptic co-medication (16.6 μg/ml). Conclusion: Levetiracetam monitoring has a role in patients on antiepileptic polypharmacy and for confirmation of compliance.



How to cite this article:
Mathew B S, Fleming D H, Thomas M, Prabha R, Saravanakumar K. An initial experience with therapeutic drug monitoring of levetiracetam as reported from a pediatric clinical setting in India.Neurol India 2012;60:146-149


How to cite this URL:
Mathew B S, Fleming D H, Thomas M, Prabha R, Saravanakumar K. An initial experience with therapeutic drug monitoring of levetiracetam as reported from a pediatric clinical setting in India. Neurol India [serial online] 2012 [cited 2020 Oct 26 ];60:146-149
Available from: https://www.neurologyindia.com/text.asp?2012/60/2/146/96382


Full Text

 Introduction



Levetiracetam has been shown to be effective in patients with refractory partial seizures with and without secondary generalization. [1],[2] In the study by Bootsma and colleagues, [3] 65.6% of patients continued to be on the drug one year after the initiation of therapy. Similar efficacy and safety profile has been reported in the pediatric population with refractory partial seizures. [4] Levetiracetam has favorable pharmacokinetics: linear pharmacokinetics, minimum protein binding (10%) [5],[6] and mainly renal elimination with only 24% metabolized by hydrolysis without involvement of CYP3A pathways. [7] Thus drug interaction with other antiepileptic co-medications is likely to be less as most often patients with refractory seizures are likely to be on polypharmacy. However, Perucca et al., have reported a 43% higher apparent total body clearance (Cl/F-where Cl is clearance and F is systemic availability of the oral dose) for levetiracetam in patients co-treated with enzyme-inducing antiepileptic drugs than in patients treated with valproate. [8] Similar were the observations in the study by Freitas-Limaa and colleagues, who reported an increase in Cl/F of 25% in levetiracetam patients treated with inducing antiepileptic drugs. [9] Earlier studies also reported large inter-individual variability in the levetiracetam concentrations within groups treated with similar dosages. [10] Unlike the older antiepileptic drugs, therapeutic drug monitoring (TDM) of the newer antiepileptic drugs has not been a regular practice. [11],[12] Earlier studies have shown restricted benefit of TDM in patients receiving levetiracetam and a clear-cut margin for trough concentration in relation to clinical improvement has not been demonstrated. [10] Giroux and colleagues [13] have reported a lack of correlation between serum levetiracetam concentration and clinical efficacy in the pediatric population. In this study 60% of the responders had serum concentration ranging from 5-40 μg/ml. This study includes a pediatric population from an Indian tertiary care referral hospital and the aims include: to find out if there is any difference in the serum concentration of levetiracetam between patients who were on enzyme inducers and those who were on enzyme inhibitors and to demonstrate any possible correlation between serum levetiracetam concentration and clinical efficacy.

 Materials and Methods



The study was approved by the Institutional Review Board of our hospital. The main inclusion criterion was children above one year of age with seizures and on levetiracetam for a minimum period of three months. Informed consent from the parents was taken before including them in the study. Patients were continued on the same antiepileptic medication and dosage which they were receiving before recruitment into the study. The enzyme inducers included carbamazepine, phenobarbitone, phenytoin and oxcarbazepine and enzyme-inhibiting agent was valproate. The questionnaire administered to the parent included demographic details, concurrent antiepileptic drugs and dosing regimen for levetiracetam, which included duration of treatment, both from the initiation of levetiracetam and also from the recent dose adjustment. Details of seizure frequency in the last six months prior to initiation of levetiracetam and for the last three months on the recent dose of levetiracetam were noted. Patients were considered as responders when the seizure frequency had been reduced by >50% of baseline frequency. In case of the patients in whom levetiracetam dose had been changed in the last three months, they would be followed up by telephone until the completion of three months. At the time of recruitment, the morning trough sample was collected, serum was separated and stored at -70 degrees for analysis. Samples were extracted by solid-phase extraction and analyzed by high-performance liquid chromatography. Imprecision calculated as interday coefficient of variation for the quality control of 10 μg/ml was 6.4%.

 Results



A total number of 69 children who were initiated on levetiracetam for at least three months prior to the study were recruited: 40 patients with generalized epilepsy, 26 patients with focal epilepsy and 3 with focal epilepsy with secondary generalization. The underlying etiology of epilepsy was: idiopathic in 26, hypoxic ischemic encephalopathy in 17 and premature birth in 10. All recruited patients were diagnosed prior to the study visit and were treated for seizures.

[Table 1] shows median age and weight of the patients, levetiracetam dosing, and serum concentration measurements. All patients except two were prescribed levetiracetam at a dose above 20 mg/kg, with a maximum dose of 66.7 mg/kg. Except for two patients, one with 44.9 and the other 53.8 μg/ml, the remaining patients had serum concentration less than 36.0 μg/ml. Inter-patient variability in serum levetiracetam concentration was calculated based on serum concentration normalized to a dose of 40 mg/kg (measured serum concentration/actual dose in mg/kg)*40 mg/kg. Inter-patient variability in dose-normalized serum levetiracetam concentration was 63.3%. [Figure 1] illustrates the range of serum levetiracetam concentration at varying total dose/day in milligrams. Correlation (r) between concentration and age, body weight and dose in mg/kg was 0.19, 0.12 and 0.29 respectively.{Figure 1}{Table 1}

[Table 2] shows the serum concentration based on the presence and absence of interfering concomitant antiepileptic medications. Four patients on lamotrigine and one on topiramate were included in the group without interfering antiepileptic drug. The median serum concentration with inducers was 50% lower than for patients with inhibitors and 56% lower than for patients without interfering co-medication. Mann-Whitney U test confirmed a statistically significant difference in serum concentrations between inducers and inhibitors (P value=0.008) and also between inducers and those without interfering antiepileptic co-medication (P value= 0.004). However, the median levetiracetam dose in patients without interfering co-medication, with inducers and with inhibitors was not significantly different and was 40, 41.7 and 40 mg/kg respectively. There were 55 responders and eight non-responders. Documentation of seizure frequency in six patients was not possible as the parents were unable to convey these details. With respect to seizure improvement with levetiracetam, 87.3% of patients responded. There was no significant difference in the median serum levetiracetam concentration between the responders and non-responders, which was 14.7 μg/ml (range and 95% CI was <1-53.8 and 12.3-16.5) and 12.0 μg/ml (range and 95% CI was 2.2-8.6 and 7.3-17.3) μg/ ml respectively. Statistically, there was no definite serum concentration to differentiate between responders and non-responders, P value= 0.332 by Mann-Whitney U test and the area under receiver operating characteristics curve analysis (ROC) was 0.630. The median dose in responders and non-responders was 40 mg/kg and 43 mg/kg respectively.{Table 2}

 Discussion



The median dose in responders in our study was similar to that reported by Gallentine and colleagues. [14] A large inter-individual variability was noted in serum levetiracetam concentration in this population, which was similar to the observations in the other studies. [10],[15] In our study 60.9% of patients were on concurrent interfering antiepileptic medication, with more patients on enzyme inhibitors than on enzyme inducers. Except for two patients in the inducer category who were on oxcarbazepine, all the others had serum levetiracetam concentration less than 8.5 μg/ml. This observation raises the doubt whether oxcarbazepine should be considered as an inducer of levetiracetam metabolism. Median serum concentrations of levetiracetam in patients on valproate or on non-interfering antiepileptic co-medications were higher than in patients on enzyme inducers. Two patients on enzyme inhibitors had negligible concentrations. It is possible that these two patients may be cases of poor drug compliance. Of the remaining patients concurrently treated with valproate, 10.3% of patients had serum concentrations less than 10 μg/ml. These observations are in agreement with the observation made by May and colleagues. [15] In their study levetiracetam serum concentrations were not significantly different when patients were on monotherapy or on concurrent valproate. [15]

In this study seizure frequency prior to starting levetiracetam could only be obtained from history which could have recall bias. In order to eliminate this bias, we recommend that future prospective studies be done with well-maintained seizure diary for accurate analysis. Only 50.9% of responders had median serum levetiracetam concentration greater than 14.7 μg/ml, whereas 63.6%, 78.2%, and 87.2% of responders had serum levetiracetam concentration above 12, 10, and 8 μg/ml respectively. Of the non-responders, 75% of patients had concentrations more than 10 μg/ml. Since there was an overlap in concentrations between responders and non-responders, a therapeutic range could not be defined. The possibility of a lower limit of 8 or 10 μg/ml in serum levetiracetam concentration as a starting guideline to assist clinical management may be suggested. However, to confirm statistical significance for the above, it would require future studies with more number of patients.

The results of this study are in agreement with the first TDM study in the pediatric population, which reported absence of a correlation between serum concentration and seizure control. [13]

Our study highlights the possibility of unexpected alteration of levetiracetam concentration when antiepileptic medications, in particular inducers are concurrently used and also the need to increase the dosage in non-responders who use inducers along with levetiracetam. The role of individualizing levetiracetam dosing based on maintaining sequential intra-patient measurements with minimum variability is yet to be investigated. Sequential intra-patient data can be a useful tool to confirm compliance. To conclude, TDM of levetiracetam may not be necessary in routine clinical practice but has a role in non-responders, on antiepileptic polypharmacy and with doubtful compliance.

 Acknowledgments



We thank Ms Daisy Rani for her technical expertise in monitoring levetiracetam concentration and Dr Babu LN for his contribution. Also special thanks to the Research Committee of the Christian Medical College, Vellore for funding the study.

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