Elsevier

Epilepsy Research

Volume 74, Issue 1, April 2007, Pages 60-69
Epilepsy Research

Prospective assessment of levetiracetam pharmacokinetics during dose escalation in 4- to 12-year-old children with partial-onset seizures on concomitant carbamazepine or valproate

https://doi.org/10.1016/j.eplepsyres.2006.12.005Get rights and content

Summary

Purpose

To assess the multiple-dose pharmacokinetics of levetiracetam and its major metabolite ucb L057 in children with partial-onset seizures and determine whether it is affected by adjunctive carbamazepine or valproate. To correlate levetiracetam concentrations in plasma and saliva and to assess its safety and clinical response.

Methods

Design was an open-label, multicenter study. Twenty-one children (4–12 years old) with epilepsy taking carbamazepine (13) or valproate (8) received adjunctive levetiracetam. Levetiracetam was initiated at 20 mg/(kg day) and titrated at 2-week intervals to 40 and then 60 mg/(kg day). Twelve-hour pharmacokinetics were determined at the end of each 2-week period. Efficacy was estimated from the partial seizure frequency per week and Global Evaluation Scale.

Results

Levetiracetam was rapidly absorbed following oral dosing, with median tmax of 0.5 h. Dose proportional increases were observed for Cmax and AUC(0–12) over the dose range; t1/2 was 4.9 h. Pharmacokinetics of levetiracetam and ucb L057 were not markedly different with concomitant carbamazepine or valproate; clearance was only 7–13% faster and AUC was decreased by only 15–24% in those on carbamazepine compared to valproate. Levetiracetam did not affect trough carbamazepine or valproate. Concentration in saliva and plasma were strongly correlated. Seizure frequency declined by 50% or more in 43% of subjects in the intent-to-treat population (n = 21) and in 56% of those with seizures at baseline (n = 16). Marked or moderate improvement occurred in 80% and 75% of patients based on Global Evaluation Scale ratings by investigators and parents/guardians, respectively. Levetiracetam was well tolerated.

Conclusion

Levetiracetam exhibits simple pharmacokinetics in children, with rapid absorption and dose-proportional kinetics. Small but not clinically relevant differences were observed between subjects receiving carbamazepine and valproate, suggesting significant dose adjustment is usually not necessary. This substantiates prior assessments that levetiracetam clearance is higher in children than adults, necessitating a higher dose in children on a mg/kg basis, and suggests it is useful add-on therapy for children with partial-onset seizures regardless of baseline therapy.

Introduction

Epilepsy is a common neurologic problem in children (Hauser, 1992, Hauser, 1994, Bourgeois, 1995). Generalized seizures predominate in the first years of life, but by age 5 years, partial-onset seizures are also common (Hauser, 1992). Despite advances in drug treatment, one of every four children with epilepsy suffers from intractable seizures, and many others experience significant treatment-related side effects (Pellock, 1999). Antiepileptic drugs (AED) are first evaluated in adults because adults represent a large, stable, and homogeneous population compared to children. Once an AED has been found to be safe and effective in adults, then it is necessary to evaluate safety, efficacy, and pharmacokinetics in children.

Levetiracetam is a novel AED with a unique mechanism of action and simple pharmacokinetic and clinical profiles that have been well characterized in adults (Welty et al., 2002). Levetiracetam binds selectively and with high affinity to synaptic vesicle protein 2A (SV2A) (Lynch et al., 2004), a protein involved in the coordination of synaptic vesicle exocytosis and neurotransmitter release (Crowder et al., 1999). The binding affinity of a series of levetiracetam analogs for SV2A correlates with seizure protection in an animal epilepsy model, suggesting that levetiracetam may protect against seizures by modulating SV2A (Noyer et al., 1995, Fuks et al., 2003). Adjunctive levetiracetam was well tolerated and effective in reducing seizure frequency in adults with partial-onset seizures in randomized controlled clinical trials (Ben-Menachem and Falter, 2000, Cereghino et al., 2000, Shorvon et al., 2000, Otoul et al., 2005).

Levetiracetam is effective and well tolerated in children. In a multicenter, randomized, double-blind, placebo-controlled study of children aged 4–16 years with treatment-resistant partial-onset seizures, nearly half (44.6%) of subjects on levetiracetam had ≥50% reductions in seizure frequency, and 7% became seizure-free (Glauser et al., 2006). Levetiracetam was well-tolerated, with adverse events rates comparable to placebo (Glauser et al., 2006). Similar results have been reported in open-label studies and in a retrospective chart review of add-on levetiracetam in children with refractory seizures (Glauser et al., 2002, Wheless and Ng, 2002, Lagae et al., 2003, Lagae et al., 2005, Coppola et al., 2004, Tan and Appleton, 2004). In these studies, levetiracetam was effective against a variety of seizure types, particularly partial-onset seizures.

The pharmacokinetics of levetiracetam are well characterized in adults, but information on pharmacokinetics in children is limited. The clearance of levetiracetam was about 30–40% faster in children than adults in a single-dose (20 mg/kg), multicenter, open-label pharmacokinetic study of levetiracetam in children aged 6–12 years who were receiving a stable dose of one concomitant AED for partial seizures (Pellock et al., 2001).

The present study was designed to document the pharmacokinetics of levetiracetam following administration of multiple and escalating doses (20, 40, and 60 mg/(kg day)) of levetiracetam, to children with partial-onset seizures and inadequately controlled by monotherapy with carbamazepine or valproate. The doses were selected to correspond with the recommended dose range in adults, and taking into account the higher clearance previously reported in children (Pellock et al., 2001). Although pharmacologically inactive, the carboxylic acid metabolite of levetiracetam, ucb L057, was also determined in plasma because it is the major metabolite produced in humans. The present study was also designed to evaluate potential bidirectional pharmacokinetic interactions between levetiracetam and either carbamazepine or valproate. Concomitant monotherapy with these AEDs was selected, because they are commonly used to treat epilepsy in children, and carbamazepine is a hepatic enzyme-inducer, while valproate is an inhibitor of hepatic drug metabolizing enzymes (Anderson, 1998). A third study objective was to explore the usefulness of saliva as a non-invasive surrogate of plasma for levetiracetam monitoring and pharmacokinetic investigation in children. Saliva and plasma levetiracetam concentrations were recently shown to be highly correlated in healthy adults (Lins et al., 2007).

Section snippets

Study design

This was an open-label, multicenter study (UCB study number N01010) consisting of a 2-week selection period, 6-week titration period, and 4-week withdrawal period (Fig. 1). The study protocol and informed consent form received institutional review board approval before any patient was enrolled. The study was conducted in accordance with the principles of the Declaration of Helsinki and guidelines for Good Clinical Practice, and in compliance with federal regulations of the U.S. Food and Drug

Patient demographics and disposition

The PP population consisted of eight boys and six girls, with an average age of 10.2 ± 2.2 years (Table 1). The subjects were initially diagnosed with epilepsy at an average age of 5.3 ± 3.8 years and had epilepsy for a mean duration of 4.9 ± 3.7 years. Most had complex partial seizures (64%) and/or partial seizures with secondary generalization (50%). All but one female subject were premenarchal. The subgroup treated concomitantly with valproate (n = 8) tended to consist of more Hispanic subjects,

Pharmacokinetic measurements

This study demonstrates that levetiracetam displays linear and dose-proportional pharmacokinetics over the dose range of 20–60 mg/(kg day) in children aged 4–12 years who are concomitantly receiving carbamazepine or valproate. The mean linearity parameter β (90% CI) for Cmax was 1.040 (0.912–1.167) and for AUC(0–12) was 1.058 (0.983–1.113). In both cases, the 90% CI was well within the prospectively defined critical range of dose proportionality. Although the upper limit of the critical range was

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