Pharmacokinetic profile of levetiracetam

Abstract

Levetiracetam is a novel orally active antiepileptic drug with a unique preclinical profile. It has a high therapeutic index and potential antiepileptogenic effects. Results of clinical trials indicate activity in partial-onset and generalized seizures. The pharmacokinetic profile of levetiracetam closely approximates the ideal characteristics expected of an antiepileptic drug, with good bioavailability, rapid achievement of steady-state concentrations, linear and time-invariant kinetics, minimal protein binding, and minimal metabolism. The major metabolic pathway of levetiracetam is not dependent on the hepatic cytochrome P450 system, and levetiracetam does not inhibit or induce hepatic enzymes to produce clinically relevant interactions. Sixty-six percent of an administered levetiracetam dose is eliminated unchanged in urine; 24% is metabolized to an inactive metabolite that is detectable in blood and is also excreted in urine. Total body clearance of levetiracetam is decreased in patients with renal impairment, and doses should be modified according to creatinine clearance values. Levetiracetam is not appreciably protein-bound, nor does it affect the protein binding of other drugs. Thus, because of its minimal protein binding and lack of hepatic metabolism, the risk of drug interactions is very low. Levetiracetam has a wide margin of safety and patient-friendly pharmacokinetics that distinguish it from other currently available antiepileptic drugs. This profile may facilitate the clinical management of patients with epilepsy by providing a safer and less-complicated therapeutic strategy.

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.