Levetiracetam Clinical Pharmacokinetic Monitoring in Pediatric Patients with Epilepsy

Abstract

Levetiracetam is a broad-spectrum antiepileptic drug (AED) with a unique mechanism of action. Older AEDs can cause serious short- and long-term adverse drug reactions and complications, rendering them undesirable to use in pediatric patients. Characteristics that make levetiracetam a near-ideal AED include its broad spectrum of activity, good tolerability profile, and minimal drug-drug interactions. Clinical pharmacokinetic monitoring (CPM) is often recommended in pediatric patients for certain AEDs due to large interindividual pharmacokinetic differences and unpredictable drug disposition. Our objective was to determine whether monitoring levetiracetam concentrations is warranted for pediatric patients with epilepsy, using a previously published 9-step decision-making algorithm. A literature search of the MEDLINE (1946-August 2016), EMBASE (1974-August 2016), CENTRAL, and Google Scholar databases was performed to identify relevant English-language articles and answer the questions posed in the algorithm for levetiracetam CPM in pediatric epilepsies. Additional articles were identified from a manual bibliographic review of the relevant literature. We found that levetiracetam CPM met some criteria of the algorithm: levetiracetam is an appropriate adjunctive or monotherapy for pediatric patients with either focal or generalized seizures; it is readily measurable in plasma, with an appropriate degree of sensitivity, accuracy, and precision; it exhibits interindividual variation in pharmacokinetics; often, its pharmacologic effect cannot be easily measured; and the duration of therapy is expected to be long-term. However, important criteria not met include the following: there is no clear evidence for a concentration-response relationship for efficacy or toxicity; the proposed therapeutic range of 12-46 μg/mL is not well-defined and is generally considered as wide. Thus, clinical decision making is unlikely to be affected as a result of routine levetiracetam CPM. In general, routine CPM of levetiracetam cannot be recommended for pediatric patients with epilepsy. However, CPM may be beneficial in select cases, such as patients in whom noncompliance is suspected, those who have severe overdoses, those switching between product brands, or patients for whom an 'individual therapeutic concentration' is documented. Nonetheless, in the majority of pediatric patients with epilepsy, measurement of levetiracetam concentrations is not expected to yield a therapeutic benefit. Thus, clinical assessment and judgment, without measuring drug concentrations, remain the monitoring strategy of choice for levetiracetam therapy.

Comparison of levetiracetam with phenytoin for the prevention of intravenous busulfan-induced seizures in hematopoietic cell transplantation recipients

“…More recently, there have been reports of the use of levetiracetam as a prophylaxis against busulfan-induced seizures in pediatrics; however, there is little information regarding its use in adults [ 5 , 10 , 11 ]. The pharmacokinetic features of levetiracetam, including approximately 100% bioavailability and linear pharmacokinetics, enable its usage without therapeutic drug monitoring (TDM) [ 12 , 13 ]. Additionally, the drug has no effect on cytochrome P450 metabolic enzymes [ 14 ].…”

Comparison of levetiracetam versus phenytoin/fosphenytoin for busulfan seizure prophylaxis at a pediatric institution

“…In addition to similar safety and efficacy to phenytoin, levetiracetam has a simple twice-daily dosing regimen that does not require loading doses or therapeutic drug monitoring and has no significant drug-drug interactions which can lead to increased busulfan clearance or affect other potential medications patients may require. 10,11,[13][14][15][16]…”

“…Overall, our study demonstrates levetiracetam is safe and effective for seizure prophylaxis in pediatric patients and we would propose that levetiracetam be considered as the seizure prophylaxis agent of choice for pediatric patients undergoing HSCT with conditioning regimens which contain busulfan. In addition to similar safety and efficacy to phenytoin, levetiracetam has a simple twice‐daily dosing regimen that does not require loading doses or therapeutic drug monitoring and has no significant drug‐drug interactions which can lead to increased busulfan clearance or affect other potential medications patients may require 10,11,13‐16 …”

The role of chronobiology in drug-resistance epilepsy: The potential use of a variability and chronotherapy-based individualized platform for improving the response to anti-seizure drugs

“…In most pediatric patients with epilepsy treated with levetiracetam, there is no strong indication for a concentration-response association with efficacy or toxicity. It has been suggested that concentrations of levetiracetam do not correlate with the therapeutic value, implying that clinical judgment, without assessing drug concentrations, should be the main strategy [203]. The C3435 T polymorphism of the MDR1 gene has been proposed as a marker to predict drug-resistance in epilepsy [204].…”