Antiepileptic Drugs, 5th Edition

Levetiracetam

41

Chemistry, Biotransformation, Pharmacokinetics, and Drug Interactions

Philip N. Patsalos FRCPath, PhD

Senior Lecturer in Clinical Pharmacology, Department of Clinical and Experimental Epilepsy, Institute of Neurology; and Director, Department of Pharmacology and Therapeutics Unit, National Hospital of Neurology and Neurosurgery, London, United Kingdom

Levetiracetam is derived from a series of nootropic drugs and is the (S)-enantiomer of the ethyl analog of piracetam. It is structurally unrelated to other antiepileptic drugs and has unique preclinical and clinical profiles. Because levetiracetam is ineffective in the classic screening models for acute seizures, its antiepileptic efficacy was nearly overlooked. Its potent anticonvulsant effects against a variety of seizure types in animal models of chronic epilepsy combined with its significant clinical efficacy and highly favorable therapeutic index, suggest that levetiracetam will be a useful antiepileptic drug (1,2).

CHEMISTRY AND METABOLIC SCHEME

Levetiracetam, (S)-α-ethyl-2-oxo-l-pyrrolidine acetamide (Figure 41.1), has a molecular weight of 170.21 and an empirical formula of C₈H₁₄N₂O₂. It is a white to off-white powder with a bitter taste and faint odor. Levetiracetam is highly soluble in water (104.0 g/100 mL), freely soluble in chloroform (65.3 g/100 mL) and methanol (53.6 g/100 mL), soluble in ethanol (16.5 g/100 mL), sparingly soluble in acetonitrile (5.7 g/100 mL), and practically insoluble in n-hexane. It is formulated for clinical use as 250-, 500-, and 1,000-mg film-coated tablets. Blood concentrations of levetiracetam can be measured either by using gas chromatography with nitrogen-phosphorus detection after solid-phase extraction or by isocratic high-performance liquid chromatography with ultraviolet detection after extraction with dichloromethane (3,4).

ABSORPTION

Absorption of levetiracetam after oral ingestion of doses ranging from 250-mg to 5,000-mg is rapid, linear, and almost complete (>95%), with peak plasma concentrations (C_max) occurring approximately 1 hour later (T_max). Although an intravenous formulation of levetiracetam is not available, absolute oral bioavailability is considered to be essentially 100%, and the extent of absorption is independent of dose. A study comparing 500-mg tablets and two 250-mg capsules of levetiracetam in healthy volunteers after single and multiple doses has shown that the two formulations are bioequivalent. Levetiracetam can be ingested without regard to meal times because although food coingestion slows the rate of levetiracetam absorption, the extent is unaffected (5).

DISTRIBUTION

In humans and in the rat, levetiracetam is not bound to plasma proteins. The volume of distribution of levetiracetam is approximately 0.5 to 0.7 L/kg. Steady-state plasma concentrations are reached within 48 hours. Human tissue distribution data are not available. In the rat, mouse, rabbit, and dog, levetiracetam rapidly distributes into tissues with concentrations approximating those in blood, with the exception of lower concentrations in the lens and adipose tissue and higher levels in the kidneys. In rats, levetiracetam rapidly and readily crosses the blood-brain barrier to enter both brain extracellular and cerebrospinal fluid compartments (6,7). Levetiracetam brain concentration increases linearly and dose-dependently and does not display brain region specificity, as indicated by its comparable distribution in the extracellular fluid of the hippocampus and frontal cortex (7).

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ROUTES OF ELIMINATION

The major route of elimination of levetiracetam is renal (Table 41.1). Clearance is rapid, so that within 48 hours approximately 93% of an oral dose is eliminated. It undergoes minimal metabolism (hydrolysis of the acetamide group) to three inactive metabolites: one major carboxylic acid metabolite (L057; 24% of dose; Figure 41.1) and two minor metabolites (~3% of dose). Other unknown components account for 0.6% of the dose. Thus, approximately 66% of an administered dose is recovered as unchanged levetiracetam in urine, whereas the inactive metabolites account for 27%. The metabolic pathway of the two minor inactive metabolites has not yet been determined. Hepatic autoinduction is not a feature of levetiracetam metabolism (8). Enantiomeric interconversion has not been observed for levetiracetam or its primary metabolite in the dog (9). Whether enantiomer interconversion occurs in humans is unknown.

ROUTES OF EXCRETION

As mentioned previously, the major route of elimination for levetiracetam is through urine (66% of administered dose is eliminated unchanged and 27% is excreted in urine as inactive metabolites) (10). Excretion by the fecal route accounts for only 0.3% of administered dose. Renal clearance of levetiracetam occurs at a rate of 40 mL/min/1.73 m² (0.6 mL/min/kg), indicating excretion by glomerular filtration and partial subsequent tubular reabsorption. Renal clearance of the primary metabolite L057 is approximately 4.2 mL/min/kg, indicating active tubular secretion in addition to glomerular filtration.

CLEARANCE AND HALF-LIFE

Healthy Subjects

The elimination half-life of levetiracetam in healthy, young volunteers ranges from 6 to 8 hours, and is independent of dose or frequency of administration (5).

Comedicated Epileptic Patients

In patients taking enzyme-inducing antiepileptic drugs (phenytoin, phenobarbitone, primidone, or carbamazepine)

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or valproic acid, the elimination half-life of levetiracetam is comparable with that of subjects receiving levetiracetam alone. During the clinical evaluation of levetiracetam, patients comedicated with tiagabine, topiramate, oxcarbazepine, or zonisamide were excluded, and thus the effects of these antiepileptic drugs on the elimination half-life of levetiracetam are unknown.

Children

In a series of 24 children (aged 6 to 12 years) with partial-onset seizures, the elimination half-life of levetiracetam (after a single oral dose of 20 mg/kg) was 5-7 hours and was independent of sex (11). The half-life of the L057 metabolite was approximately 8 hours. C_max and area under the curve (AUC) values (adjusted to a dose of 1 mg/kg) were approximately 30% to 40% lower than that in adults, although the renal clearance was similar. The apparent total body clearance was approximately 30% to 40% higher than that in adults. Over a 24-hour interval, 52% of the administered dose was excreted in urine as levetiracetam and 9% as L057. Based on these data, a maximum maintenance dosage equivalent to 130% to 140% of the usual adult dose is recommended.

Elderly Subjects

The elimination half-life of levetiracetam in the elderly increases to between 10 and 11 hours (12,13). A study of 16 elderly subjects (mean age, 77 years; range, 61 to 88 years) receiving 1,000 mg/day for 10 consecutive days suggests that the longer half-life of levetiracetam is in fact the consequence of a reduction in creatinine clearance consequent to an age-related decline in renal function (5). Thus, it is appropriate for levetiracetam dose to be adjusted in elderly patients according to their creatinine clearance.

Patients with Renal Impairment

Because the renal clearance of levetiracetam and its metabolite L057 correlate directly with creatinine clearance, the elimination half-life of levetiracetam is increased in patients with renal impairment and in patients with severe hepatic impairment and concurrent renal impairment (hepatorenal syndrome) (12,13). At steady-state, the C_max of levetiracetam is higher than that of healthy subjects. AUC values increase with decreasing renal function, so that in patients with mildly to moderately impaired renal function, values can be nearly twice those with normal renal function. Also, the elimination half-life of levetiracetam is prolonged. In patients with very mild to moderately severe renal impairment (creatinine clearance = 20 to 89 mL/min/1.73 m²), total clearance has been observed to decrease by 35% to 60%. Thus, dosage should be reduced in patients with impaired renal function.

In a series of five patients with anuric end-stage renal disease undergoing hemodialysis, the pharmacokinetic profiles of levetiracetam and L057 over 104 hours after a single 500-mg dose were determined (14). Levetiracetam was rapidly and completely absorbed after a single 500-mg dose. However, clearance was only 30% of that in healthy subjects, and during dialysis its elimination half-life was approximately 3 hours, whereas in the periods between dialysis its half-life was 25 hours. Dialyzer extraction efficiency was high, leading to the removal of 50% of levetiracetam during a 4-hour session. L057 also was rapidly removed from plasma. Therefore, for patients with end-stage renal disease maintained on hemodialysis, levetiracetam should be supplemented by 30% to 50% of the usual daily dose on dialysis days.

Patients with Hepatic Impairment

The pharmacokinetics of levetiracetam and L057 are unaffected by mild to moderate hepatic impairment (15). This is consistent with the fact that the liver contributes little to the metabolism of levetiracetam. In patients with severe hepatic impairment, levetiracetam and L057 elimination half-life and AUC values were observed to be increased twofold to threefold, and the total-body clearance of levetiracetam was reduced by >50%. However, these changes are most likely the consequence of concurrent mild to moderate renal impairment (hepatorenal syndrome) rather than liver impairment per se. Thus, dosage adjustments may not be necessary in patients with hepatic impairment.

RELATIONSHIP BETWEEN SERUM CONCENTRATION AND DOSE

In healthy volunteers, levetiracetam C_max and AUC values increase dose-dependently and linearly in the range of 500 to 5,000-mg (5). In multiple dose-ranging studies, levetiracetam has exhibited predictable, linear, and dose-proportional steady-state pharmacokinetics, with steady-state concentrations occurring within 2 days of initiation of dosing. After a single 1,000-mg and repeated 1,000-mg twice-daily doses, levetiracetam plasma C_max values typically are 23 and 43 µg/mL, respectively.

RELATIONSHIP BETWEEN PLASMA CONCENTRATION AND EFFECT

The relationship between levetiracetam plasma concentration and its antiepileptic activity or its adverse effects profile has not been formally investigated.

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INTERACTION PROFILE

The interaction potential of levetiracetam has been extensively investigated in studies conducted in vitro, in healthy volunteers, and in patients with epilepsy. Because levetiracetam is not metabolized in the liver or bound to plasma proteins, it has a very low potential for drug interactions (16). However, drugs excreted by tubular secretion potentially may interact with both levetiracetam and L057 because both undergo tubular secretion.

Because by far the most clinically significant pharmacokinetic drug-drug interactions involve the induction or inhibition of cytochrome P450 (CYP) enzymes (17,18), the effect of levetiracetam on the activity of hepatic CYP enzymes was investigated using in vitro human liver microsomal markers (19). Levetiracetam and its primary metabolite, L057, at concentrations exceeding five times the plasma therapeutic concentration, were evaluated for their potential inhibitory effect on 11 different drug-metabolizing enzymes [CYP3A4, CYP1A2, CYP2C19, CYP2E1, CYP2C9, CYP2D6, epoxide hydrolase, uridine 5′-diphos-pho-glucuronyltransferase^*1 (UGT1^*6), UGT1^*1, and UGT(pl 6.2)]. Enzyme activities were unaffected. Furthermore, using primary cultures of rat hepatocytes, levetiracetam did not induce CYP activity (19). These results suggest that levetiracetam is unlikely to produce clinically relevant interactions through the induction or inhibition of CYP- or UGT-mediated reactions.

Antiepileptic Drugs

Levetiracetam does not appear to interact with other antiepileptic drugs, and overall the pharmacokinetic parameters of levetiracetam during polytherapy with antiepileptic drugs are comparable to those of subjects receiving levetiracetam alone (20). In various add-on clinical studies of levetiracetam, plasma concentrations of antiepileptic drugs were compared before and during administration of levetiracetam (13,21, 22, 23, 24, 25). Meta-analysis has revealed that levetiracetam does not affect the concentrations of carbamazepine, clobazam, clonazepam, diazepam, gabapentin, lamotrigine, phenobarbital, phenytoin, primidone, valproic acid, and vigabatrin. However, in one study, the addition of levetiracetam to the polytherapy regimens of patients with epilepsy resulted in a 27% to 52% increase in phenytoin concentrations, with one patient requiring a reduction in the dosage of phenytoin because of neurotoxicity (13). Because phenytoin is a commonly prescribed antiepileptic drug, its interaction potential with levetiracetam has been investigated further using a sensitive technique that employs deuterium-labeled phenytoin (26). Six male patients taking phenytoin as monotherapy for the treatment of their epilepsy were investigated; however, no interactions between levetiracetam and phenytoin were observed.

In a formal study of 16 healthy volunteers designed to investigate the effect of valproic acid (a potent inhibitor of hepatic metabolism) on the pharmacokinetics of levetiracetam, it was observed that valproic acid did not affect the extent of oral absorption or the metabolism and urinary excretion of levetiracetam (27).

The interaction potential between levetiracetam and felbamate, tiagabine, topiramate, and zonisamide has not been investigated.

Other Drugs

Numerous studies have been undertaken to determine possible interactions between levetiracetam and various commonly used drugs, including warfarin, digoxin, the oral contraceptives ethinylestradiol and levonorgestrel, and probenecid (5). Coadministration of levetiracetam (2,000 mg/day) with warfarin did not affect the pharmacokinetics or pharmacodynamics of warfarin, as determined by measuring prothrombin time. Conversely, the pharmacokinetics of levetiracetam were unaffected by warfarin.

The pharmacokinetics of digoxin and levetiracetam were assessed using a double-blind, placebo-controlled, two-way crossover design in 11 healthy adults (7 male) (28). Electrocardiograms also were recorded. At the doses investigated, no relevant pharmacokinetic or pharmacodynamic interactions were observed between levetiracetam (2,000 mg/day) and digoxin (0.25 mg/day).

Contraceptive efficacy appears not to be affected by levetiracetam (29). Coadministration of levetiracetam (500 mg twice daily) and a low-dose monophasic oral contraceptive (0.3 mg ethinylestradiol, 0.15 mg levonorgestrel) in 18 women over 21 days did not alter plasma estrogen or progesterone values or bleeding patterns compared with placebo.

Concomitant administration of levetiracetam (2,000 mg/day) both as single doses and multiple doses with probenecid (500 mg four times daily) did not affect the pharmacokinetic parameters of levetiracetam (5). However, the plasma concentration of its primary metabolite, L057, increased 2.5-fold consequent to a 61% decrease in tubular secretion. Although the clinical relevance of elevated concentrations of L057 is not known, caution is warranted with concurrent use of levetiracetam and probenecid. The effect of levetiracetam on probenecid has not been studied. Furthermore, the interaction potential between levetiracetam and other drugs undergoing tubular secretion has not been investigated.

SUMMARY

Pharmacokinetic studies of levetiracetam have been conducted in healthy volunteers, in patients of all ages with

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epilepsy, and in certain special populations. Results of these studies indicate that levetiracetam has a favorable pharmacokinetic profile characterized by excellent oral absorption and bioavailability and a mean elimination half-life of 7 hours. Levetiracetam is not bound to plasma proteins and is not metabolized in the liver, so it is not expected to be associated with significant pharmacokinetic interactions. Indeed, to date, no clinically relevant interactions with levetiracetam have been identified. Because levetiracetam is primarily excreted unchanged in urine, dosage adjustments are necessary for patients with moderate to severe renal impairment.

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