Lessons learnt from therapeutic drug monitoring of levetiracetam

NN Rege 
 Department of Pharmacology, Era's Lucknow Medical College, Lucknow, Uttar Pradesh, India

Correspondence Address:
Dr. N N Rege
Department of Pharmacology, Era's Lucknow Medical College, Lucknow, Uttar Pradesh
India

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Therapeutic drug concentration monitoring (TDM) plays a valuable role in guiding the management of patients with antiepileptic drugs. It is a valuable tool for clinicians to optimize drug regimens for an individual patient, achieving seizure suppression whilst minimizing adverse effects of the prescribed drug.[1] It also sheds light on why the patient is not responding as expected to a given dose regimen, which may be nonadherence to treatment, interindividual variations in its pharmacokinetics (PK), or interactions with co-medications. However, for using this tool successfully in clinical practice, one needs to have a simple, accurate, reproducible, and inexpensive analytical technique to measure drug concentration. Further, mere measurement of drug concentrations is not enough; their clinical interpretation is equally crucial. The latter requires adequate knowledge of PK, sampling time, history of prescribed drugs, and patient's clinical conditions.[1],[2] Any publication on analysis of data generated from TDM backed by appropriate clinical observations and context helps other clinicians to verify their own experiences with the drug and guide their own practice. Such publications are therefore welcome in the literature. In the current issue of this journal, Munshi et al.[3] have reported their experience in developing and validating a modified HPLC-UV method for the estimation of serum levetiracetam levels and assessing its usefulness in epileptic patients.

Levetiracetam was introduced in 1999 as an antiepileptic and today it is a very commonly used drug.[4],[5] It has several advantages over other older antiepileptic drugs. For example, it gets completely absorbed. It binds minimally to the plasma protein, gets excreted mainly through kidney by glomerular filtration and its clearance shows a good correlation with creatinine clearance. Its PK profile is linear. It requires twice-a-day dosing and there is a relative lack of drug-drug interaction.[6],[7] Moreover, it is a broad spectrum anti-epileptic and can be used to treat multiple types of epilepsies, in both adults and children.[4] It has a rapid onset of action and relatively fewer adverse effects.[7] This makes it useful in acute seizure management as well as in critically ill patients having seizures.[4]

In the initial decade of its introduction, the role of TDM for levetiracetam was not established.[1] However, subsequently, when its usage increased, recommendations for TDM evolved.[4]

Numerous chromatographic methods for the quantitation of levetiracetam in serum have been described in the literature.[1],[8] But the assay methods undergo constant development and modification to make them more robust, rapid, and cost-effective. This is especially needed when the resources are limited so that benefits derived from TDM can be extended to more and more patients. Whenever a new assay is developed, it needs to be validated using specified parameters. Munshi et al.[3] have described reasons for the development of the new method, its advantages over others, and the process of validation. This part of the article is more useful for those who wish to set up such an assay technique; however, understanding this background is also important for clinicians to be confident about the results which they will be using to make clinical decisions.

Munshi et al.[3] have considered the reference range as 5–41 μg/mL established by the Norwegian Association of Clinical Pharmacology based on the comparisons of reference ranges available in the literature, those used by certain centers outside Norway and Norwegian laboratory databases.[9] The “reference range” means a range of concentrations, below the lower limit of which a therapeutic response may not occur, and above the stated upper limit adverse effects are likely to occur. Throughout the article, this range has been termed as the “therapeutic range”. Ideally, therapeutic range is specified for a given patient and is the range of drug concentrations associated with the best achievable response in that person. However, if the reference range is derived from extensive research as in the above Norwegian study,[9] therapeutic ranges of many individual patients will be within the reference range. Some may derive optimal benefit at concentrations outside the range or some may get ADR within the range.[1] The readers will precisely notice this in the present article. Based on the clinical experience of six years involved in this study, it may be possible for the authors to revise the used reference range for Indian patients.

The authors have painstakingly documented all the clinical details of the patients attending their TDM out-patient department from 2015 to late 2020. They have designed specific TDM proforma so that important points for critical analysis of estimated concentrations would not be missed while taking the patient's history. In addition, for the study purpose, they defined what is meant by 'good' seizure control and compliance. All these real-life data collected over six years from 1383 patients have helped in the interpretation of drug concentrations. Perhaps it would have been more appropriate if they would have mentioned sampling time in relation to dose ingestion (because levetiracetam has a relatively short half-life) and also the time lag between sample collection and serum separation. Levetiracetam gets hydrolyzed in the whole blood. So separation of serum as soon as possible is essential to avoid lowering of concentration in vitro.[1]

Routine TDM of levetiracetam is not recommended and doses can be guided by clinical outcomes, either seizure control or occurrence of adverse effects.[1] The present study also reveals that in 1107 patients (of the total 1383; 80.04%) the values remained within the therapeutic range and in 82.4% of patients there was good control over seizures. However, the drug has a wide range of alteration in specific populations, namely, in children, elderly, pregnant women, non-responders, and patients taking more than one antiepileptic drug, especially those which are enzyme inducers.[8],[10] In such cases TDM of levetiracetam is recommended. TDM is also useful in detecting compliance.[2]

In the present study, analysis of data, though descriptive, has been done in various categories- according to age, in pregnancy, when a patient has received more than one antiepileptic, and those showing poor seizure control. Care was also taken to check compliance. The findings of the authors are in line with the observations reported elsewhere and confirm the relevance of TDM in children, the elderly, pregnancy, those getting other antiepileptic agents which are either cytochrome P 450 inducers or inhibitors, and non-responders or poor-responders to therapy.

As per the literature levetiracetam is better tolerated. In the present study too ADRs were noted in 203 patients (14.67%). But the important finding was that 46 patients from this group reduced the dose on their own. Usually, such patients may or may not inform the physician about alterations in doses done by them. But as shown in the present study, if low levels are detected through TDM, then such finding helps the physician to probe into the issue and detect non-compliance.

As mentioned above, the authors have used descriptive statistics and presented before us the percentages in various categories or subpopulations of patients (e.g., according to age, concentration relation with respect to therapeutic range, seizure control, compliance, monotherapy vs. polytherapy, etc.). Though simple to analyze the data, interpretation of findings is a little tedious because the influence of multiple variables coexists. It would have been better to use multivariate regression analysis to get more meaningful conclusions. Being a public service activity, TDM of levetiracetam will be a continuous activity for the authors. Hence they can plan a prospective study with long-term follow-up of individual patients and also include a subpopulation with compromised renal function, which needs close monitoring. This would perhaps result in future additional publications from the group that can shed more light on the relationship between levetiracetam concentration and clinical response especially when PK variability is anticipated due to the coexistence of multiple factors. Whether conducting TDM is cost-effective or not can also be judged based on how it supports timely clinical decisions. As technology continues to advance, newer assay techniques can be developed and compared with the existing one. In short, therapeutic drug monitoring facility provides a wider scope for clinical research that benefits patients, clinicians and the institute.

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