Review articlePharmacokinetic profile of levetiracetam: toward ideal characteristics
Introduction
Although 80% of patients with newly diagnosed epilepsy are rendered seizure-free, overall, seizures remain inadequately controlled in 30–50% of patients with epilepsy using currently available antiepileptic drugs Kälviäinen & Riekkinen 1995, Rogawski & Porter 1990, Sander 1993. The difficulty in achieving total control of seizures is largely related to the adverse effects associated with antiepileptic drugs and the adverse effects that can result from pharmacokinetic or pharmacodynamic interactions in polytherapy regimens Patsalos 1994, Patsalos 1999a. Moreover, most antiepileptic drugs do not prevent epileptogenesis, the process by which epilepsy develops, or protect against the progression of neuronal damage Kälviäinen & Riekkinen 1995, Silver et al. 1991. Therefore, the development of safer and more effective antiepileptic therapies with more favorable adverse effect profiles, better pharmacokinetic characteristics, and the ability to improve the prognosis of epilepsy is needed.
Levetiracetam ((S)-α-ethyl-2-oxo-1-pyrrolidine acetamide) (Fig. 1) is a novel orally active antiepileptic drug, structurally unrelated to other antiepileptics and with a unique preclinical profile. Despite a lack of effect in classical screening models for acute seizures (i.e., maximal electroshock seizure test and pentylenetetrazol seizure test), levetiracetam exhibits potent antiepileptic effects against a variety of seizure types in animal models of chronic epilepsy De Deyn et al. 1992, Gower et al. 1995, Klitgaard et al. 1998, Löscher & Hönack 1993, Löscher et al. 1998. Its efficacy in kindling models, in which there is repeated application of an initially subconvulsive electrical stimulus to induce the development of epilepsy and subsequent predisposition to seizures, suggests that unlike most antiepileptic drugs, levetiracetam has antiepileptogenic properties at clinically used doses (Löscher et al., 1998). Results of preclinical and clinical trials indicate that levetiracetam has efficacy in partial-onset and generalized seizures Sharief et al. 1996, Shorvon 1998.
Although the mechanism of action is not fully understood, in vitro assays performed on crude membranes suggest that levetiracetam selectively binds to brain cell membranes in the CNS in a reversible, saturable, and stereoselective fashion (Noyer et al., 1995). Ligand-binding assays and direct neurochemical analysis reveal no significant interactions with the benzodiazepine-γ-aminobutyric acid-chloride complex or excitatory amino acid receptors (Sills et al., 1997). Unlike many other antiepileptic agents, levetiracetam has a very wide therapeutic index, with a large separation between the doses necessary to control seizures and those producing toxicity (Klitgaard et al., 1998). In addition, antiepileptic effects are maintained following chronic administration without signs of tolerance or withdrawal after cessation of treatment.
In recent years, the importance of pharmacokinetics in antiepileptic drug therapeutics has been increasingly recognized, and the characterization of the clinical pharmacokinetic profile of a new antiepileptic drug has become an integral and early component of drug development. Pharmacokinetic considerations are especially relevant with antiepileptic drugs for several reasons. Patients with epilepsy generally require chronic therapy, and, therefore, a dosing strategy that enhances compliance is essential. Many patients will be prescribed two or more antiepileptic drugs, oftentimes at the highest possible doses. Thus, it is desirable that the drugs do not cause interactions that can precipitate toxicity. In addition, all patients with chronic epilepsy can be expected to develop during their lifetime concomitant nonepilepsy-related diseases that require additional drug therapy, increasing the potential for drug interactions and toxicity. The elderly population is particularly susceptible.
In addition to unique pharmacological and clinical effects, levetiracetam also has a unique and highly desirable pharmacokinetic profile. The purpose of this review is to summarize the “ideal” pharmacokinetic characteristics of an antiepileptic drug and compare this information to the pharmacokinetic profile of the novel antiepileptic drug levetiracetam.
Section snippets
Pharmacokinetics of the ideal antiepileptic drug
The pharmacokinetic characteristics of the ideal antiepileptic drug include rapid absorption after oral ingestion, good bioavailability with rapid achievement of steady-state concentrations, linear kinetics, minimal or no protein binding, a half-life offering once- or twice-daily dosing, absence of drug-drug interactions, and no metabolism Browne 1998, Patsalos 1999b. Linear kinetics are preferred because plasma drug concentrations correlate directly with dose. Thus, drug concentrations are
Pharmacokinetics of levetiracetam
The pharmacokinetic profile of levetiracetam has been evaluated in healthy volunteers; adult, pediatric, and elderly patients with epilepsy; and patients with renal and hepatic impairment. Overall, levetiracetam has a very favorable pharmacokinetic profile, with rapid absorption following oral administration, excellent bioavailability, quick achievement of steady-state concentrations, linear kinetics, and minimal plasma protein binding (Table 3). In addition, levetiracetam is not hepatically
Pediatric population
The pharmacokinetic profile of levetiracetam in children aged 6–12 years with partial-onset seizures was determined following administration of a single oral dose of 20 mg/kg.3 After 24 hr, the elimination half-life of levetiracetam was determined to be ∼6 hr and was independent of gender. The apparent total body clearance was ∼30–40% lower than that in adults although the renal clearance of the metabolite was similar. In contrast, values for Cmax and AUC, adjusted to a dose of 1 mg/kg, were
Drug interaction profile of levetiracetam
Studies conducted in vitro in healthy volunteers and in patients with epilepsy indicate that levetiracetam has a very low potential for drug interactions4 Giuliano et al. 1996, Patsalos et al. 1994. Because levetiracetam is not metabolized in the liver or significantly protein bound (<10%), concomitantly administered drugs are unlikely to produce clinically relevant interactions with levetiracetam. Nevertheless, drugs excreted by tubular secretion have been shown to inhibit the urinary
Conclusions
Pharmacokinetic studies of levetiracetam have been conducted in healthy volunteers, in patients of all ages with epilepsy, and in certain special populations (e.g., patients with renal or hepatic impairment). Results of these studies indicate that levetiracetam has a very favorable pharmacokinetic profile, with properties pertaining to that of the ideal antiepileptic drug (Table 7). In addition, based on the pharmacokinetic rating system, levetiracetam achieves nearly the maximum attainable
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