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