Clin Pharmacokinet 2004; 43 (11): 707-724 0312-5963/04/0011-0707/$31.00/0

REVIEW ARTICLE

© 2004 Adis Data Information BV. All rights reserved.

Clinical Pharmacokinetics of Levetiracetam Philip N. Patsalos1,2 1 2

Pharmacology and Therapeutics Unit, Department of Clinical and Experimental Epilepsy, Institute of Neurology/The National Hospital for Neurology and Neurosurgery, London, UK The National Society for Epilepsy, Chalfont Centre for Epilepsy, Chalfont St Peter, UK

Contents Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 707 1. Physical and Chemical Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 710 2. Analytical Techniques . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 710 3. Pharmacokinetics in Adults . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 710 3.1 Absorption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 711 3.2 Distribution and Plasma Protein Binding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 713 3.3 Metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 713 3.4 Excretion and Elimination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 714 4. Pharmacokinetics in Children . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 714 5. Pharmacokinetics in Elderly Subjects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 714 6. Pharmacokinetics in Patients with Renal Impairment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 715 7. Pharmacokinetics in Patients with Hepatic Impairment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 715 8. Drug Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 715 8.1 Pharmacokinetic Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 716 8.1.1 In Vitro Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 716 8.1.2 Studies in Healthy Volunteers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 716 8.1.3 Studies in Patients with Epilepsy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 717 8.2 Pharmacodynamic Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 718 9. Therapeutic Drug Monitoring . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 718 10. Administration Strategies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 719 11. Rationale for a Twice-Daily Administration Strategy for Levetiracetam . . . . . . . . . . . . . . . . . . . . . . . . 719 12. Comparison of Pharmacokinetics of Levetiracetam with Those of Other Antiepileptics . . . . . . . . . 720 13. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 721

Abstract

Since 1989, eight new antiepileptic drugs (AEDs) have been licensed for clinical use. Levetiracetam is the latest to be licensed and is used as adjunctive therapy for the treatment of adult patients with partial seizures with or without secondary generalisation that are refractory to other established first-line AEDs. Pharmacokinetic studies of levetiracetam have been conducted in healthy volunteers, in adults, children and elderly patients with epilepsy, and in patients with renal and hepatic impairment. After oral ingestion, levetiracetam is rapidly absorbed, with peak concentration occurring after 1.3 hours, and its bioavailability is >95%. Co-ingestion of food slows the rate but not the extent of absorption. Levetiracetam is not bound to plasma proteins and has a volume of distribution of

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Patsalos

0.5–0.7 L/kg. Plasma concentrations increase in proportion to dose over the clinically relevant dose range (500–5000mg) and there is no evidence of accumulation during multiple administration. Steady-state blood concentrations are achieved within 24–48 hours. The elimination half-life in adult volunteers, adults with epilepsy, children with epilepsy and elderly volunteers is 6–8, 6–8, 5–7 and 10–11 hours, respectively. Approximately 34% of a levetiracetam dose is metabolised and 66% is excreted in urine unmetabolised; however, the metabolism is not hepatic but occurs primarily in blood by hydrolysis. Autoinduction is not a feature. As clearance is renal in nature it is directly dependent on creatinine clearance. Consequently, dosage adjustments are necessary for patients with moderate to severe renal impairment. To date, no clinically relevant pharmacokinetic interactions between AEDs and levetiracetam have been identified. Similarly, levetiracetam does not interact with digoxin, warfarin and the low-dose contraceptive pill; however, adverse pharmacodynamic interactions with carbamazepine and topiramate have been demonstrated. Overall, the pharmacokinetic characteristics of levetiracetam are highly favourable and make its clinical use simple and straightforward.

Initially, the treatment of epilepsy usually comprises drug treatment with antiepileptic drugs (AEDs) and, subsequently, for a select few who are intractable to such drug treatment, neurosurgical treatment. During the past decade there has been a substantial impetus in the drug treatment of epilepsy and this has been the consequence of the exponential introduction of a crop of new AEDs (figure 1). The long-established, generally available AEDs (carbamazepine, ethosuximide, phenobarbital, phenytoin, primidone and valproate) can render approximately 80% of newly diagnosed patients seizure-free when administered as monotherapy regimens.[1] However, these patients may experience numerous drug-related problems such as idiosyncratic reactions and acute and chronic CNS adverse effects, and the teratogenic potential of all these AEDs is a significant practical problem for patients planning to have families. For the remaining 20% of patients with severe treatment-refractory epilepsy, little benefit is achieved from the use of these AEDs as intolerable adverse effects occur. Furthermore, because polytherapy regimens are commonly prescribed in an attempt to control seizures, adverse effects of AEDs can be exacerbated by resultant pharmacokinetic/pharmacodynamic interactions.[2] © 2004 Adis Data Information BV. All rights reserved.

In addition, numerous profound and clinically unfriendly pharmacokinetic characteristics have been identified with these AEDs, including: (i) common hepatic metabolic pathways that can be readily inhibited or induced; (ii) production of pharmacologically active metabolites; (iii) saturable metabolism; (iv) saturable plasma protein binding; (v) autoinduction; and (vi) narrow therapeutic indices whereby the doses associated with a desirable therapeutic response are close to doses associated with undesirable toxic effects. Therefore, there has been a need for new AEDs, not only to improve the prognosis of patients with chronic intractable epilepsy, but also for new AEDs with simple pharmacokinetic characteristics. The pharmacokinetic characteristics of a drug serve to determine ease of clinical use and indeed patient compliance with a drug regimen. Furthermore, the efficacy and adverse effect profile of a drug are directly dependent on its pharmacokinetics, which consequently impact on the acceptance of the drug by the patient. During the past decade, numerous pharmacokinetic characteristics have been identified as being ideal in relation to AEDs; these are summarised in table I.[3,4] Compared with the longestablished AEDs, the new generation of AEDs Clin Pharmacokinet 2004; 43 (11)

Levetiracetam

709

18

PB to CLB = 9 AEDs = 70 years

OXC, LEV

VGB to LEV = 8 AEDs = 11 years 16

TGB ZNS

14

TPM GBP

Number of AEDs

12

LTG VGB

10 CLB VPA, CZP

8 DZP

6

CBZ ETS

4

PRM PHT

2 0 1900

PB

1920

1940

1960

1980

2000

2020

Year of introduction Fig. 1. Introduction of antiepileptic drugs (AEDs) into clinical practice. It took 70 years for the introduction of the first nine AEDs into clinical practice, but just 11 years for the subsequent eight AEDs. CBZ = carbamazepine; CLB = clobazam; CZP = clonazepam; DZP = diazepam; ETS = ethosuximide; GBP = gabapentin; LEV = levetiracetam; LTG = lamotrigine; OXC = oxcarbazepine; PB = phenobarbital; PHT = phenytoin; PRM = primidone; TGB = tiagabine; TPM = topiramate; VGB = vigabatrin; VPA = valproic acid; ZNS = zonisamide.

(gabapentin, lamotrigine, levetiracetam, tiagabine, topiramate, oxcarbazepine, vigabatrin and zonisamide) are clearly associated with significantly more desirable pharmacokinetic characteristics.[5] Indeed, the latest AED to be licensed for clinical use, levetiracetam (Keppra®)1, is considered to have pharmacokinetic characteristics that are almost ideal.[4] Levetiracetam is licensed for use as adjunctive therapy for the treatment of patients with partial seizures with or without secondary generalisation that are refractory to other established first-line AEDs.[6] However, there is increasing evidence that it also has efficacy in patients with generalised epilepsy.[7,8] Because levetiracetam is ineffective in the classical screening models for acute seizures, its antiepileptic efficacy was nearly overlooked. Its significant clinical efficacy, highly favourable thera1

peutic index and simple pharmacokinetic characteristics are already establishing levetiracetam as a very useful AED.[9-12] The purpose of this review is to summarise the current understanding of the pharmacokinetic characteristics of levetiracetam. Data reviewed include those from healthy volunteers, and from adults, children and elderly patients with epilepsy. Data from patients with renal and hepatic impairment, and those receiving concomitant medication with other AEDs and other non-AED drugs, are also reviewed. Animal data are only presented when considered necessary to complement data not yet available in humans. A final section is devoted to placing the pharmacokinetic characteristics of levetiracetam in relation to the pharmacokinetic characteristics of other clinically available AEDs.

The use of trade names is for product identification purposes only and does not imply endorsement.

© 2004 Adis Data Information BV. All rights reserved.

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Table I. Ideal pharmacokinetic characteristics for an antiepileptic drug Characteristic

Comment

Rapid absorption after oral ingestion

Allows rapid onset of efficacy

Complete oral absorption

Good bioavailability

Rapid penetration of the blood-brain barrier and entrance into the brain

Allows rapid onset of efficacy

Linear pharmacokinetics

This results in minimal interpatient variability in blood concentrations and, consequently, efficacy

Minimal plasma protein binding

Fewer clinically significant protein binding displacement interactions, and also minimises complications with regard to interpretation of therapeutic drug monitoring

No induction or inhibition of hepatic enzymes

Minimises interaction potential

No auto-induction properties

This results in linear pharmacokinetics

Renal elimination is preferable to hepatic metabolism

Less interpatient variability in blood concentrations; formation of pharmacologically active metabolites is avoided

Elimination half-life of 12–24h

This is long enough to allow once- or twice-daily administration (this increases compliance), but is not so long that steady-state concentrations take an excessive time to achieve (this permits relatively rapid changes in drug dosages)

No drug interactions

Prescribing the drug is simplified

1. Physical and Chemical Properties Levetiracetam, (S)-α-ethyl-2-oxo-1-pyrrolidine acetamide (figure 2), is the (S)-enantiomer of the ethyl analogue of piracetam and as a pyrrolidone derivative it shares a similar chemical structure to numerous nootropic drugs.[13] It is structurally unrelated to other AEDs, with an empirical formula of C8H14N2O2 and a molecular weight of 170.21. Levetiracetam is a white to off-white powder with a bitter taste and faint odour. It is highly soluble in water (0.104 g/mL), freely soluble in methanol (0.054 g/mL) and chloroform (0.065 g/mL), soluble in ethanol (0.016 g/mL), sparingly soluble in acetonitrile (0.006 g/mL) and practicably insoluble in n-hexane. Levetiracetam is available as film-coated tablets containing 250, 500, 750 and 1000mg of levetiracetam, although not all tablet forms are available in every country. Tablet excipients include maize starch, povidone K30, talc, colloidal anhydrous silica and magnesium stearate. A liquid formulation for oral ingestion and an intravenous formulation are in development. © 2004 Adis Data Information BV. All rights reserved.

2. Analytical Techniques Seven analytical techniques have been described for the measurement of levetiracetam in blood and other biological material. The first involves the use of gas chromatography with nitrogen-phosphorus detection after solid phase extraction.[14] Three high performance liquid chromatographic techniques are available.[15,16] One technique involves an isocratic analysis using UV detection after extraction with dichloromethane,[16] the second involves the use of electrospray ionisation mass spectroscopy detection, whilst the third involves the use of diode array detection.[16,17] Another technique involves an enantioselective analysis of levetiracetam using gas chromatography and ion-trap mass spectrometry.[18] Finally, there is a microemulsion electrokinetic chromatographic technique which allows the concurrent quantitation of levetiracetam and other antiepileptic drugs (e.g. phenobarbital, primidone lamotrigine, phenytoin and carbamazepine)[19] and a capillary electrophoresis technique.[20] 3. Pharmacokinetics in Adults Table II summarises the pharmacokinetic characteristics of levetiracetam. Overall, the pharmacokinetics of levetiracetam are comparable among Clin Pharmacokinet 2004; 43 (11)

Levetiracetam

711

healthy male and female subjects, healthy adult Caucasians and Asians, and adult patients with epilepsy.[4] However, compared with adults, the pharmacokinetic characteristics of levetiracetam in children and the elderly show some differences.

levetiracetam 1500mg twice daily, the corresponding values for trough and Cmax are 94 (range 41–200) μmol/L and 265 (range 212–370) μmol/L, respectively. More recently, two studies have reported that levetiracetam dose and blood concentrations are linearly related.[21,22] The first study was cross-sectional in design and was undertaken as part of a 1-year postmarketing surveillance of levetiracetam in 71 patients with focal and generalised epilepsies.[21] The second, more extensive study involved the pooled analysis of blood concentration data from 590 patients who had participated in various phase III randomised controlled trials of levetiracetam.[22]

3.1 Absorption

Levetiracetam is rapidly and almost completely (>95%) absorbed following oral ingestion with peak plasma concentrations (Cmax) occurring approximately 1 hour later (tmax). After single-dose ingestion by healthy fasting volunteers, Cmax and area under the plasma concentration-time curve (AUC) values display dose linearity in the therapeutic range of levetiracetam 500–5000mg (figure 3).[4] In multiple dose-ranging studies, levetiracetam has been observed to exhibit predictable, linear and dose-proportional steady-state pharmacokinetics, with steady-state concentrations occurring within 2 days of initiation of administration. Thus, after administration of levetiracetam 500mg twice daily, mean trough plasma concentrations of 35 (range 18–59) μmol/L are attained with a mean Cmax of 100 (range 59–147) μmol/L. For levetiracetam 1000mg twice daily, the corresponding values for trough and Cmax are 70 (range 29–218) μmol/L and 188 (range 135–235) μmol/L, respectively. For

The exact bioavailability of levetiracetam is not known and must await the development of an intravenous formulation of the drug. Nevertheless, the absolute oral bioavailability of levetiracetam is considered to be essentially 100% and the extent of absorption is independent of dose. Furthermore, since co-ingestion of food only slows the rate of levetiracetam absorption without affecting the extent, levetiracetam can be ingested without regard to meal times.[4] When levetiracetam is co-ingested with an enteral nutrition formulation, a modest 27% reduction in Cmax values is observed.[23] The clinical significance of this effect is not known. Levetiracetam N CH3CH2 H

O

C CONH2

34% of dose is metabolised by hydrolysis primarily (>99%) in blood

Two metabolites of unknown structure (~3% of dose) N CH 3CH 2 H

O

C COOH

LO57 deaminated metabolite (24% of dose) Fig. 2. The structural formula of levetiracetam and its primary pharmacologically inactive metabolite L057.

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Table II. Pharmacokinetic characteristics of levetiracetam Characteristic

Parameter value

Comments

Absorption

tmax 1.3h

Absorption is rapid

Food interaction

tmax delayed; Cmax unaffected

Levetiracetam can be ingested without regard for meals

Bioavailability

Good (>95%)

As there is no intravenous formulation, the bioavailability value is an estimate

Protein binding

Not protein bound

Protein binding displacement interactions with other highly protein bound drugs cannot occur

Distribution

Vd = 0.5–0.7 L/kg

Primarily distributed in body water. Readily penetrates the brain where distribution appears ubiquitous

Dose linearity

Plasma concentrations increase in proportion to dose over the clinically relevant range up to

Administration strategies are straightforward

5000mg Time to steady state

24–48h

Permits rapid dose changes

Metabolism

Nonhepatic; 24% of dose metabolised to the inactive metabolite L057

As most clinically significant pharmacokinetic interactions occur at the site of hepatic metabolism, levetiracetam is unlikely to be associated with such interactions

Route of elimination

Renal

Interpatient variability in levetiracetam plasma concentrations can be expected to be minimal

healthy adult volunteer

6–8h

patients are comedicated with other AEDs;

adults with epilepsya

6–8h

however, dosage adjustment will be

children with epilepsya

5–7h

necessary in children and the elderly

elderly volunteers

10–11h

Plasma elimination half-life

Dosage adjustments are not necessary when

Clearance

If dosage adjustments are necessary, they

adults

30 mL/min/1.73m2 (0.6 mL/min/kg)

children

40 mL/min/1.73m2 (0.8 mL/min/kg)

elderly

25 mL/min/1.73m2 (0.5 mL/min/kg)

during dialysis

The half-life of drug removal is 4h

50% of the drug can be expected to be removed during a 4-hour dialysis episode

None

No significant interactions with other AEDs or digoxin, warfarin and the oral contraceptive pill

should be based on creatinine clearance

Interaction potential pharmacokinetic

pharmacodynamic animal studies

Synergistic interactions with GABAergic drugs have The clinical significance of these interactions been reported has yet to be ascertained

clinical reports

Two adverse interactions reported to date (with topiramate and carbamazepine)

Dosage reduction may be necessary during combination therapy with these AEDs

35–120 μmol/L (6–20 mg/L)

The exact relationship between plasma levetiracetam concentrations and antiepileptic/adverse effects is not established. These values relate to patients with intractable epilepsy evaluated in phase II and phase III trials of levetiracetam and in which therapeutic/adverse responses were documented

Plasma target range

a

Patients taking various hepatic enzyme-inducing AEDs and also valproate, which is a known hepatic enzyme inhibitor.

AEDs = antiepileptic drugs; Cmax = maximum concentration; tmax = time to maximum concentration; Vd = volume of distribution.

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Clin Pharmacokinet 2004; 43 (11)

Levetiracetam

Steady-state plasma concentrations are reached within 24–48 hours of initiation of therapy. Human tissue distribution data are not available, but levetiracetam readily and rapidly enters the cerebrospinal fluid compartment with tmax values of 3–5 hours.[24] The volume of distribution (Vd) of levetiracetam is 0.5–0.7 L/kg, a value close to that of plasma water. Levetiracetam is not bound to plasma proteins. In rats, mice, rabbits and dogs, levetiracetam rapidly distributes into tissue with concentrations approximating those in blood, with the exception of lower concentrations in the lens and adipose tissue, and higher concentrations in the kidneys. In rats, levetiracetam rapidly and readily crosses the blood-brain barrier to enter both brain extracellular and cerebrospinal fluid (CSF) compartments.[25,26] Uptake is independent of multidrug transporters P-glycoprotein (Pgp) or the multidrug resistant family protein (MRP) such as MRP1 and MRP2.[27] At equilibrium, the CSF/serum levetiracetam concentration ratio mirrors that of the serum free fraction of levetiracetam, suggesting that levetiracetam concentrations in sera directly reflect concentrations in the brain. Furthermore, levetiracetam brain concentrations increase linearly and dose-dependently and do not display brain region specificity, as indicated by its comparable distribution in the extracellular fluid of the hippocampus and frontal cortex.[26] A single case report suggests that levetiracetam may accumulate in breast milk, since breast milk levetiracetam concentrations were three times greater than that observed in the mother’s serum.[28] Breast milk alimentation was associated with the child (a boy) becoming increasingly hypotonic; levetiracetam was still detectable in the child’s serum 96 hours after the mother had stopped breastfeeding. 3.3 Metabolism

Approximately 34% of levetiracetam is metabolised and 66% of an administered dose is recovered as unchanged levetiracetam in urine.[4] However, unlike other AEDs that are metabolised, the meta© 2004 Adis Data Information BV. All rights reserved.

bolism of levetiracetam does not involve the hepatic cytochrome P450 (CYP) system. The major pathway involves the enzymatic hydrolysis of the acetamide group to produce three pharmacologically inactive metabolites; one major carboxylic acid metabolite (L057; 24% of dose) and two minor metabolites (~3% of dose [figure 2]). The metabolic pathway of the two minor inactive metabolites has recently been proposed.[29] Other unknown components account for only 0.6% of the dose. Thus, about 27% of an administered dose is recovered as inactive metabolites in urine. In dogs, enantiomeric interconversion has not been observed for levetiracetam or its primary metabolite.[30] Whether enantiomer interconversion occurs in humans is unknown. The primary site for the hydrolysis of levetiracetam appears to be the blood.[16] An in vitro study comparing human whole blood and liver homogenate clearly shows that levetiracetam is hydrolysed to LO57, but that liver homogenate is responsible for very little hydrolysis. Thus, after 6 hours of incubation (levetiracetam 200 μmol/L), liver homogenate hydrolysis represented only 0.6% of that seen by whole blood.[16] Further characterisation of the metabolism of levetiracetam has revealed that its hydrolysis is inhibited by paraoxon, a broad spectrum inhibitor of B-esterases, but not by other B-esterase-type inhibitors specific for cholinesterases and/or carboxylesterase (physostigmine, metoclopramide) or A-esterase inhibitors (edetic acid [EDTA], chloromercuribenzoate). As this inhibition

Plasma levetiracetam concentration (μmol/L)

3.2 Distribution and Plasma Protein Binding

713

5000mg 3500mg 2000mg 1000mg 500mg

720 600 480 360 240 120 0 0

5

10

15

20

25

Time (h)

Fig. 3. Levetiracetam plasma concentration-time profiles after the oral ingestion of levetiracetam 500–5000mg by healthy volunteers.[4]

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profile resembles that observed for the hydrolysis of tazarotene, it can be concluded that a type B esterase, distinct from the classical cholinesterases and carboxylesterases, is involved in the metabolism of levetiracetam.[31] Levetiracetam autoinduction does not appear to be a feature of levetiracetam hydrolysis.[32] 3.4 Excretion and Elimination

The kidneys are the primary organ responsible for the excretion of levetiracetam, and excretion via the faecal route accounts for only 0.3% of the administered dose. Of an administered dose, 66% is eliminated unchanged and 27% is excreted in urine as inactive metabolites.[4] Following oral administration, levetiracetam is rapidly cleared, with approximately 93% of the drug excreted within 48 hours. Renal clearance of levetiracetam occurs at a rate of 30 mL/min/1.73m2 (0.6 mL/min/kg), indicating excretion by glomerular filtration and partial subsequent tubular reabsorption. Renal clearance of the primary metabolite L057 is approximately 210 mL/min/1.73m2 (4.2 mL/min/kg), indicating active tubular secretion in addition to glomerular filtration. The elimination half-life (t1/2β) of levetiracetam is independent of dose or frequency of administration. Sex has no important influence on levetiracetam t1/2β values, although values tend to be shorter in females (7.4 hours [95% CI 6.8, 8.0]) than in males (8.8 hours [95% CI 8.1, 9.7]).[22] In healthy young volunteers, t1/2β values are 6–8 hours.[4] In patients taking enzyme-inducing AEDs (phenytoin, phenobarbital, primidone or carbamazepine) there appears to be a modest effect on the pharmacokinetics of levetiracetam. Thus, compared with those patients comedicated with AEDs not considered to affect CYP activity (e.g. gabapentin, lamotrigine and vigabatrin) t1/2β values are <25% smaller (7.9 hours [95% CI 7.4, 8.5] vs 8.6 hours [95% CI 6.7, 11.9]). In contrast, patients taking valproic acid (valproate sodium) [a potent hepatic enzyme inhibitor] have moderately higher levetiracetam t1/2β values (11.5 hours [95% CI 9.1, 15.5]).[22] It should be noted that the effect of tiagabine, topiramate, oxcarbazepine, felbamate and zonisamide on the t1/2β of leve© 2004 Adis Data Information BV. All rights reserved.

tiracetam is unknown, because during the clinical evaluation of levetiracetam, patients comedicated with these AEDs were excluded. However, since all these AEDs undergo hepatic CYP metabolism and levetiracetam does not, it is unlikely that these AEDs will significantly affect the elimination of levetiracetam. 4. Pharmacokinetics in Children Using a multicentre, open-label study design, the pharmacokinetics of levetiracetam were investigated in a series of 24 children aged 6–12 years (15 boys, 9 girls) with partial seizures.[33] Levetiracetam was administered as a single dose (20 mg/kg) and all children were taking only a single concomitant AED. The t1/2β of levetiracetam was 6.0 ± 1.1 hours and that of the LO57 metabolite was 8.1 ± 2.7 hours.[33] Values were independent of sex. Cmax and AUC values (adjusted to a dose of 1 mg/kg) were approximately 30–40% lower than that in adults, whereas the renal clearance was higher. In contrast, the apparent total body clearance was approximately 30% higher (0.8 mL/min/kg) than that in adults (0.6 mL/min/kg). Approximately 52% of the administered dose was excreted in urine as levetiracetam and 9% as L057 during a 24-hour interval. Based on these data, a maximum maintenance dosage equivalent to approximately 130% of the usual adult dosage is recommended. 5. Pharmacokinetics in Elderly Subjects Because levetiracetam is renally excreted, it might be expected that in the elderly, who commonly experience a reduction in creatinine clearance (CLCR) consequent to an age-related decline in renal function, levetiracetam t1/2β values would increase. Indeed, in a study of 16 healthy elderly subjects (mean age 77 years; range 61–88 years) receiving levetiracetam 1000mg daily for 10 consecutive days, levetiracetam t1/2β values of 10–11 hours were observed.[4] Consequently, in elderly patients it is appropriate for the levetiracetam dosage to be adjusted according to their CLCR. Clin Pharmacokinet 2004; 43 (11)

Levetiracetam

6. Pharmacokinetics in Patients with Renal Impairment The renal clearance of levetiracetam and its metabolite L057 correlate directly with CLCR. Thus, the t1/2β of levetiracetam is increased in patients with renal impairment, and also in patients with severe hepatic impairment and concurrent renal impairment (hepato-renal syndrome).[4] Furthermore, at steady state, the Cmax 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 in individuals with normal renal function. The t1/2β of levetiracetam is also prolonged in these patients. Patients with very mild to moderately severe renal impairment (CLCR 20–89 mL/min/1.73m2) show 35–60% reductions in total clearance. Therefore, dosage reduction should be considered for patients with impaired renal function. In a series of five patients with anuric end-stage renal disease undergoing haemodialysis, the pharmacokinetic profiles of levetiracetam and its primary metabolite LO57 were determined over a 104hour period.[34] Following a single 500mg dose, levetiracetam was rapidly and completely absorbed. However, clearance was only 30% of that in healthy subjects and during dialysis the t1/2β of levetiracetam was approximately 3 hours, whereas in the periods between dialysis t1/2β values of approximately 25 hours were observed. Both levetiracetam and LO57 were rapidly removed from plasma and the extraction efficiency of the dialyser was high, leading to the removal of 50% of levetiracetam during a 4-hour session. Consequently, on dialysis days, patients with end-stage renal disease maintained on haemodialysis should have their levetiracetam dosage supplemented by 30–50% of the usual daily dosage. 7. Pharmacokinetics in Patients with Hepatic Impairment That the pharmacokinetics of levetiracetam and its primary metabolite LO57 are unaffected by mildto-moderate hepatic impairment is not surprising © 2004 Adis Data Information BV. All rights reserved.

715

considering that the liver appears to have essentially no role in the metabolism of levetiracetam.[35] In patients with severe hepatic impairment, levetiracetam and L057 t1/2β and AUC values were observed to be increased 2- to 3-fold and the total body clearance of levetiracetam was reduced by >50%. However, these changes are most probably the consequence of concurrent mild-to-moderate renal impairment (hepato-renal syndrome) rather than liver impairment per se. Consequently, for patients with hepatic impairment, dosage adjustments are not necessary. 8. Drug Interactions The interaction profile and propensity of a new AED to interact is of major clinical importance. AEDs are clinically evaluated as add-on treatments in patients with intractable partial seizures taking AED polytherapy, and drugs with a high propensity to interact will complicate their clinical evaluation. Furthermore, as a new AED is licensed as adjunctive therapy for patients taking AED polytherapy, at least in the first instance, a drug with a propensity to interact will complicate the way it is prescribed. The fact that interaction studies are now an integral component of preclinical and phase I and phase II development underscores the importance of drug interactions in the treatment of patients with epilepsy. Drug interactions can be divided into two types, pharmacokinetic and pharmacodynamic. Pharmacokinetic interactions are readily ascertained because they result in a change in plasma concentration consequent to changes in the processes by which drugs are absorbed, distributed, metabolised and excreted. In contrast, pharmacodynamic interactions are those that are associated with a change in the clinical status of a patient consequent to an effect at the site of drug action. Consequently, pharmacodynamic interactions occur without any change in plasma drug concentration, are difficult to quantify and are usually concluded by default. Our understanding of pharmacokinetic interactions is far greater than that of pharmacodynamic interactions, and indeed far more pharmacokinetic Clin Pharmacokinet 2004; 43 (11)

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interactions have been documented and investigated.[2] The most important clinically significant pharmacokinetic interactions are those that are associated with plasma protein (albumin) binding displacement, and hepatic enzyme inhibition and induction involving hepatic CYP isoenzymes, the latter being by far the most important.[36-38] 8.1 Pharmacokinetic Interactions

Theoretically, levetiracetam can be expected to have a very low potential for drug interaction since it is neither protein bound in blood nor metabolised in the liver. Nevertheless, the interaction potential of levetiracetam has been extensively investigated in studies conducted in vitro, in healthy volunteers and in patients with epilepsy. 8.1.1 In Vitro Studies

The in vitro effect of levetiracetam on the activity of various CYP isoenzymes was investigated using human liver microsomal markers.[39] 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 metabolising enzymes (CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4, epoxide hydrolase and uridine 5′-diphospho-glucuronyltransferase [UGT] 1*6, 1*1 and pI 6.2). Neither levetiracetam nor LO57 affected enzyme activities. Furthermore, levetiracetam did not induce CYP activity in cultures of rat hepatocytes.[39] These results suggest that neither levetiracetam nor LO57 are likely to produce clinically relevant interactions through the induction or inhibition of reactions mediated by hepatic CYP isoenzymes, epoxide hydrolase or UGT isoenzymes. The in vitro effect of valproic acid (1 mmol/L) on the hydrolysis of levetiracetam by human whole blood has been investigated.[16] Valproic acid had no effect. The fact that a type B esterase enzyme distinct from the classical cholinesterases and carboxylesterases is involved in the metabolism (hydrolysis) of levetiracetam may reveal potential interactions with levetiracetam in the future.[16] However, as this metabolic pathway is only responsible for approximately 24% of the metabolism of © 2004 Adis Data Information BV. All rights reserved.

levetiracetam, an interaction at this site is unlikely to be of major clinical significance in the majority of patients. 8.1.2 Studies in Healthy Volunteers

Numerous studies in healthy volunteers have been undertaken to determine possible interaction between levetiracetam and various commonly used drugs, including warfarin, digoxin, the oral contraceptives ethinylestradiol and levonorgestrel, probenecid and antacids.[4] In addition, the potential interaction between valproate and levetiracetam has been investigated. Using a double-blind, placebo-controlled, twoway crossover design, the effect of levetiracetam on the pharmacodynamics and pharmacokinetics of digoxin was assessed in a series of 11 healthy adults (seven males, four females, aged 19–48 years).[40] Electrocardiographic (ECG) recordings were undertaken at timed intervals. Each subject received digoxin 0.25mg once daily (0.5mg on day 1) during a 1-week run-in period, followed by two 1-week periods of coadministration of digoxin and levetiracetam (2000 mg/day) or placebo. No relevant pharmacokinetic interactions were observed between levetiracetam and digoxin at the doses investigated. Furthermore, ECG pharmacodynamic parameters did not differ significantly between levetiracetam and placebo administration.[40] The effect of levetiracetam on the pharmacokinetics and pharmacodynamics of warfarin was assessed in 26 healthy adults (18–50 years of age; 18 males, 8 females).[41] Subjects received warfarin 2.5, 5 and 7.5 mg/day plus levetiracetam 1000mg twice daily or placebo. The anticoagulant effect was measured by the international normalised ratio (INR). Levetiracetam had no significant effect on the pharmacokinetics of either (R)-warfarin or (S)-warfarin, and levetiracetam was without effect on the protein binding of warfarin. Furthermore, the INR values were not significantly affected by levetiracetam administration, and the pharmacokinetics of levetiracetam were unaffected by warfarin.[41] Coadministration of levetiracetam 500mg twice daily and a low-dose monophasic oral contraceptive (ethinylestradiol 0.03mg, levonorgestrel 0.15mg) in Clin Pharmacokinet 2004; 43 (11)

Levetiracetam

18 healthy women over a period of 21 days did not alter plasma oestrogen or progesterone values or bleeding patterns compared with placebo.[42] Furthermore, ethinylestradiol and levonorgestrel pharmacokinetic parameters were not significantly different during concomitant treatment with either levetiracetam or placebo.[42] Thus, at the doses studied, contraceptive efficacy appears not to be affected by levetiracetam. Single- and multiple-dose pharmacokinetics of levetiracetam 2000 mg/day are unaffected by probenecid when administered at a dose of 500mg four times daily.[43] However, the plasma concentration of its primary metabolite, L057, increased 2.5fold consequent to a 61% decrease in tubular secretion. Although the clinical relevance of elevated concentrations of L057 is not known, vigilance is warranted during combination therapy with levetiracetam and probenecid, particularly since the effect of levetiracetam on probenecid is also unknown. A further consideration relates to the interaction potential between levetiracetam and other drugs undergoing tubular secretion, since such drug combinations have not been investigated. Using an open-label, one-way, one-sequence crossover study, 16 healthy volunteers (ten males, six females) were investigated to ascertain the in vivo interaction potential between valproate (a potent inhibitor of hepatic metabolism) and levetiracetam.[16] The pharmacokinetics of single-dose levetiracetam 1500mg were compared before and after 8 days of administration of valproate 500mg twice daily as the enteric slow-release formulation. Valproate was without effect on levetiracetam pharmacokinetics and this was also the case with its metabolite, LO57. Furthermore, valproate did not affect the extent of oral absorption or the metabolism and urinary excretion of levetiracetam. Conversely, the steady-state pharmacokinetics of valproate were not modified by a single dose of levetiracetam 1500mg.[16] The antacids calcium carbonate and aluminium hydroxide do not affect the extent of absorption of levetiracetam.[4] © 2004 Adis Data Information BV. All rights reserved.

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8.1.3 Studies in Patients with Epilepsy

Various add-on, randomised, placebo-controlled clinical studies of adult patients with intractable epilepsy have investigated the addition of levetiracetam 1000, 2000, 3000 or 4000 mg/day on the steady-state plasma concentrations of numerous AEDs.[6,7,44-48] Levetiracetam does not appear to significantly interact with other AEDs and, overall, the pharmacokinetic parameters of levetiracetam during polytherapy with AEDs[22] are comparable to those of subjects receiving levetiracetam alone.[4] Meta-analysis has revealed that levetiracetam does not affect the concentrations of carbamazepine, clobazam, clonazepam, diazepam, gabapentin, lamotrigine, phenobarbital, phenytoin, primidone, valproic acid or vigabatrin.[49] Similar data emphasising the lack of interaction between levetiracetam and these AEDs has been reported for children with epilepsy.[50] Also, a single-dose study in patients with photosensitive epilepsy suggests that the pharmacokinetics of ethosuximide are unaffected.[51] The effect of concomitant AEDs on the levetiracetam serum (concentration) level to dose ratio (LDR) was investigated by May et al.[52] It was observed that whilst coadministered phenobarbital, lamotrigine, topiramate and bromide were without any significant effect, coadministration of phenytoin, mesuximide, carbamazepine and oxcarbazepine lowered levetiracetam LDR values by 21–29%. Valproic acid was associated with a significant 16% increase in LDR values. Although the interaction potential between levetiracetam and the AEDs felbamate, topiramate, tiagabine and zonisamide is unknown, no significant interactions should be anticipated because, although these AEDs undergo hepatic CYP metabolism, levetiracetam does not. Indeed, in a recent efficacy and safety study of levetiracetam in children, plasma concentrations of felbamate (one patient) and topiramate (four patients) were unaffected by levetiracetam, although the patient numbers were small.[50] In one study, the addition of levetiracetam to patients with epilepsy taking polytherapy regimens resulted in a 27–52% increase in phenytoin plasma concentrations, with one patient requiring a phenytoin dosage reduction because of neurotoxicity.[44] Clin Pharmacokinet 2004; 43 (11)

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Since phenytoin is a commonly prescribed AED, its interaction potential with levetiracetam has been investigated further using a sensitive technique that employs deuterium-labelled phenytoin.[53] Six male patients taking phenytoin as monotherapy for the treatment of their epilepsy were investigated. The pharmacokinetics of phenytoin were determined during phenytoin monotherapy and at approximately 12 weeks after coadministration with levetiracetam 3 g/day, using a twice daily schedule. Levetiracetam was without effect on any of the pharmacokinetic parameters determined and, thus, the authors concluded that there is no interaction between levetiracetam and phenytoin. The disparate results may be explained, perhaps, by confounding factors in unusually susceptible individuals. 8.2 Pharmacodynamic Interactions

Experimentally, levetiracetam has been associated with numerous pharmacodynamic interactions with other AEDs. In particular, it appears that the anticonvulsant efficacy of levetiracetam in animal models of seizures (e.g. audiogenic mice and amygdala-kindled rats) is substantially and synergistically enhanced by GABAergic drugs.[54-56] AEDs with such an effect include valproic acid, clonazepam, phenobarbital and carbamazepine. Furthermore, the combination of levetiracetam and diazepam in a rat model of experimental status epilepticus is also associated with anticonvulsant synergy.[57] Clinically, to date two drugs (carbamazepine and topiramate) have been associated with a possible adverse pharmacodynamic interaction with levetiracetam.[50,58] In a series of four adult patients with severe refractory epilepsy, Sisodiya et al.[58] reported that the introduction of levetiracetam led to disabling symptoms compatible with carbamazepine toxicity. One patient was taking carbamazepine as monotherapy, and symptoms in all four patients resolved after dosage reduction of carbamazepine or withdrawal of levetiracetam. It was noted that plasma concentrations of neither carbamazepine nor carbamazepine epoxide (the pharmacologically active © 2004 Adis Data Information BV. All rights reserved.

metabolite of carbamazepine) were affected by levetiracetam administration. In an open-label, multicentre study of levetiracetam in 24 children (15 male, 9 female, aged 6–12 years) with refractory epilepsy, it was reported that in four children, topiramate-related adverse events became worse upon comedication with levetiracetam.[50] The adverse events, which occurred 2 weeks after the addition of levetiracetam to their topiramate regimen, comprised decreased appetite, weight loss and nervousness, requiring a topiramate dosage reduction of 27–75%. It was noted that plasma topiramate concentrations were not affected by levetiracetam administration. 9. Therapeutic Drug Monitoring The clinical value of plasma concentration measurements has not been established for levetiracetam, since the relationship between levetiracetam plasma concentrations and clinical effect has not been ascertained. Nevertheless, based on clinical trial data for levetiracetam in adult patients taking concomitant AEDs, the target range for a daily dosage of 1000–3000mg is 35–120 μmol/L.[59] More recently, however, data reflective of clinical settings are beginning to accumulate and there is a suggestion that the plasma concentration of levetiracetam is related to the efficacy of the drug and that therapeutic monitoring of levetiracetam may be useful.[60-62] Furthermore, the target range for levetiracetam may vary and may be dependent on seizure type and intractability (e.g. it may be higher in patients with Lennox-Gastaut syndrome compared with those patients with absence seizures). For various AEDs (e.g. carbamazepine, phenobarbital and phenytoin) there is a good correlation between plasma and saliva concentrations,[63-65] and these relationships have been investigated for some of the newer AEDs (e.g. lamotrigine, oxcarbazepine and zonisamide).[66-69] As therapeutic monitoring of AEDs using saliva is considered to be particularly useful (sampling is convenient, painless and noninvasive) in paediatric patients, the elderly and those with disabilities, and generally in patients with poor venous access, the correlation of levetiracetam Clin Pharmacokinet 2004; 43 (11)

Levetiracetam

719

Table III. Levetiracetam dosage adjustment based on creatinine clearance (CLCR) calculated by the Cockcroft-Gault method Patient group

CLCR (mL/min)

Levetiracetam dose (mg) and frequency

Patients with normal renal function

>80

500–1500 bid

Mild impairment

50–79

500–1000 bid

Moderate impairment

30–49

250–750 bid

Severe impairment

<30

250–500 bid

End-stage renal disease patients undergoing dialysisa

500–1000 odb

a

A 750mg loading dose is recommended on the first day of treatment with levetiracetam.

b

Following dialysis, a 250–500mg supplemental dose is recommended

bid = twice daily; od = once daily.

concentrations between blood and saliva has recently been investigated.[70] The fact that significant correlation (r = 0.87) is found for levetiracetam would suggest that levetiracetam could be usefully monitored by means of saliva sampling. Overall, because levetiracetam has a highly favourable therapeutic index and is associated with few significant adverse effects (typically asthenia, dizziness and somnolence), routine monitoring of levetiracetam drug concentrations seems not to be necessary for the safe use of levetiracetam and administration can be readily guided by therapeutic response. It is unlikely that the management of the recently reported adverse behavioural and psychotic effects of levetiracetam[71-73] would benefit from the routine monitoring of levetiracetam drug concentrations. Nevertheless, drug monitoring may be useful in the management of patients who may overdose with the drug, and during pregnancy. A particularly useful application would be in the event that drug compliance needs confirmation. 10. Administration Strategies Levetiracetam is available in most countries as an oral preparation in tablets containing 250, 500 and 1000mg of levetiracetam. The 1000mg tablet is not available in the US, but a 750mg tablet is available. Treatment can begin at a dosage of 500mg twice daily. This dosage can be subsequently increased in 2-weekly steps of 1000 mg/day to 3000 mg/day, depending on clinical response. Steady-state pharmacokinetics are usually attained within 48 hours and the emergence of antiepileptic activity is normally evident within 3 days of treatment initiation. For children with epilepsy, preliminary data would © 2004 Adis Data Information BV. All rights reserved.

suggest that a daily maintenance dosage of levetiracetam equivalent to 130–140% of a typically effective adult daily maintenance dosage, corrected for smaller body mass (mg/kg), would be appropriate. Dosage regimens need to be adjusted based on clearance in the elderly and patients with renal impairment (table III). Patients with hepatic impairment do not need to have any dosage adjustment unless impairment is severe and associated with a CLCR of <70 mL/min. 11. Rationale for a Twice-Daily Administration Strategy for Levetiracetam As the t1/2β of a drug determines the administration frequency, and since the t1/2β for levetiracetam in adults is 6–8 hours, it would be expected that a three times daily regimen would be warranted for levetiracetam. However, throughout the clinical trials evaluation programme of levetiracetam, a highly efficacious and sustainable effect was observed with twice daily administration and indeed this is now the clinically practiced strategy. An explanation for this apparent anomaly may perhaps be forthcoming from three pieces of evidence. The first piece of evidence relates to the pharmacokinetics of levetiracetam in the CSF and brain extracellular fluid of rats,[25,26] and CSF of humans.[24] It appears that the efflux of levetiracetam from both the extracellular fluid and CSF compartments is restricted, with t1/2β values that are approximately 50% and 100% longer, respectively, than that observed in blood. In humans, CSF t1/2β values are more than three times that of blood and, Clin Pharmacokinet 2004; 43 (11)

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Table IV. Customised rating system to evaluate the pharmacokinetic profile of antiepileptic drugs (AEDs) Parametera

Score 3

2

1

speed of absorptionA

Rapid

Slow

Poor

bioavailabilityB

Very good

Good

Poor

affected by foodC

Unaffected

Slowed only

Reduced and slowed

KineticsD

Linear

Nonlinear

Nonlinear and saturable

Plasma protein bindingE

Minimal

Significant

Substantial

EliminationF

Renal

Partly renal

Nonrenal

MetabolismG

None or very little

Partial

Extensive

hepaticH

No

Partial

Substantial

inducibleI

No

Partial

Substantial

autoinducibleJ

No

Partial

Substantial

active metabolitesK

None

One

Two or more

affected by other AEDsL

No

Affected

Substantial

affects other AEDsM

No

Affected

Substantial

affected by other drugsN

No

Affected

Substantial

affects other drugsO

No

Affected

Oral absorption

Drug interactions with AEDs

with non-AEDs

AdministrationP a

Once or twice daily Three times daily Superscripted letters are used to denote the various pharmacokinetic characteristics in table V.

thus, the prolonged action in the brain of levetiracetam could be explained by its prolonged efflux from the brain compartment. The second piece of evidence relates to a study in 12 patients with photosensitive epilepsy who were administered a single oral dose (250–1000mg) of levetiracetam.[51] In those nine patients who experienced a suppression of photosensitivity or in whom photosensitivity was abolished, the effect occurred within 1 hour after drug ingestion (2 hours in one patient) and was associated with blood concentrations of 40–170 μmol/L. Of particular note, however, is that suppression lasted >6 hours (24–30 hours in two patients), at which time plasma levetiracetam concentrations were very low indeed (<18 μmol/L). Finally, the third piece of evidence relates to a transcranial magnetic stimulation study of levetiracetam in a series of six healthy subjects (five men, one women) aged 25–38 years (mean 31 years).[73] Transcranial magnetic stimulation provides a noninvasive test to assess the effect of AEDs © 2004 Adis Data Information BV. All rights reserved.

Substantial More than three times daily

on corticospinal excitability. After a single oral dose of levetiracetam 3000mg a time-dependent suppression of motor-evoked potentials amplitude was observed in all six subjects. The effect became distinct at 1 hour after levetiracetam ingestion, persisted at 6 hours and was still present at 24 hours. Thus, there is compelling evidence to suggest that levetiracetam has a long duration of action that outlasts its blood concentration. 12. Comparison of Pharmacokinetics of Levetiracetam with Those of Other Antiepileptics It is now well recognised that the pharmacokinetic properties of a drug are an important consideration in therapeutics. Indeed, the pharmacokinetic characteristics of a drug not only determine whether or not a drug will be developed and, therefore, be clinically evaluated, but, also, once the drug is licensed for clinical use, its pharmacokinetic characteristics will determine how the drug is prescribed, its efficacy and adverse effect profiles and also Clin Pharmacokinet 2004; 43 (11)

Levetiracetam

721

whether or not the patient will comply with the drug prescription.

all the new AEDs are ranked above these four vindicates the desirability and consequent development of new drugs with more simple pharmacokinetic characteristics to aid ease of clinical use. Levetiracetam and vigabatrin achieved the highest scores. One point has been deducted from levetiracetam under absorption because its rate of absorption is delayed by co-ingestion of food. A second point has been deducted under metabolism because it undergoes partial metabolism; however, metabolism is not hepatic and is non-CYP dependent, therefore it is not amenable to metabolic interactions typically associated with AEDs. Thus, compared with other AEDs currently available for clinical use, the pharmacokinetic characteristics of levetiracetam are the most desirable and closely resemble those of an ideal AED.

In order to enable direct comparison between AEDs, a semiquantitative pharmacokinetic rating system has been devised based on six pharmacokinetic characteristics.[4] In order to make this rating system more sensitive in comparing AEDs, the system has been expanded in this review to include 16 parameters (shown in table IV). A score of 3 is optimal and corresponds with the pharmacokinetic characteristics of an ideal AED, as indicated in table I. A score of 2 is satisfactory and a score of 1 is unsatisfactory. Using this rating system, the pharmacokinetic parameters of the different AEDs can be readily compared (the comparison is shown in table V). For each AED, a percentage of the perfect score is calculated by adding up the values from each category and dividing by the maximum attainable score, with a final ranking being determined. Under this system it can be seen that phenytoin and carbamazepine, the two most prescribed of the established AEDs, rated lowest with respect to favourable pharmacokinetic characteristics, mostly because of their nonlinear kinetics, extensive hepatic metabolism and high propensity to interact both with other AEDs and with non-AEDs. Indeed, it is noteworthy that all four of the long-established AEDs are ranked bottom of the list, and the fact that

13. Conclusion During the last decade, many new AEDs have been introduced into clinical practice; however, their introduction has coincided with our increased appreciation of the contribution that pharmacokinetics make in relation to drug prescribing and subsequent patient compliance. Thus, compared with the long-established AEDs, the new AEDs are associated with improved pharmacokinetic properties. Levetiracetam in particular has a highly desira-

Table V. Pharmacokinetic profile rating of the various antiepileptic drugs presently licensed worldwidea Drug

A

B

C

D

E

F

G

H

I

J

K

L

M

N

O

P

Percentage of perfect scoreb

Levetiracetam

3

3

2

3

3

3

2

3

3

3

3

3

3

3

3

3

96

Vigabatrin

3

2

3

3

3

3

3

3

3

3

3

3

2

3

3

3

96

Gabapentin

3

1

3

2

3

3

3

3

3

3

3

3

3

2

3

2

89

Topiramate

3

3

2

3

3

3

2

2

1

3

3

1

2

2

2

3

79

Ethosuximide

3

3

3

3

3

2

1

1

1

3

3

1

2

2

3

3

77

Oxcarbazepine

3

3

3

3

2

3

1

1

2

3

2

1

3

2

2

3

77

Lamotrigine

3

3

3

3

2

2

1

1

1

2

3

1

3

2

2

3

73

Tiagabine

3

2

2

3

1

2

1

1

1

3

3

1

3

2

2

2

67

Zonisamide

2

2

2

3

2

2

1

1

1

2

3

1

2

2

3

3

67

Phenobarbital

2

3

2

3

2

2

1

1

1

1

3

1

1

1

1

3

58

Valproic acid

3

3

2

2

1

1

1

1

1

2

1

1

1

1

1

3

52

Carbamazepine

2

2

2

2

2

1

1

1

1

1

2

1

1

1

1

3

50

Phenytoin

2

2

3

1

1

1

1

1

1

1

3

1

1

1

1

3

50

a

The pharmacokinetic parameters abbreviated in the column headers are described in table IV.

b

Calculated by adding up the score from each pharmacokinetic parameter and dividing by the maximum attainable score of 48.

© 2004 Adis Data Information BV. All rights reserved.

Clin Pharmacokinet 2004; 43 (11)

722

Patsalos

ble pharmacokinetic profile. Levetiracetam is rapidly absorbed, exhibits linear kinetics, is not bound to plasma proteins, is not metabolised by hepatic enzymes and undergoes renal elimination with mean t1/2β of 7, 6 and 10.5 hours in adults, children and the elderly, respectively. Levetiracetam is not associated with significant pharmacokinetic interactions with any of the currently licensed AEDs, including the hepatic enzyme-inducing AEDs (carbamazepine, phenytoin, phenobarbital and primidone) and valproic acid (a hepatic enzyme inhibitor). Also, no interaction occurs with digoxin, warfarin or the oral contraceptive (low dose) pill, and concomitant administration with these can occur without dosage adjustments. However, because levetiracetam is primarily excreted unchanged in urine, dosage adjustments will be necessary for patients with moderate to severe renal impairment. In the elderly, dosage may be best guided by CLCR. Overall, the pharmacokinetic characteristics of levetiracetam are impressive, making its clinical use much simpler than that of the other 14 AEDs currently available for the long-term treatment of patients with epilepsy. Acknowledgements The work of the author is supported by the National Society for Epilepsy, University College Hospitals NHS Trust and the Institute of Neurology, University College, London. The author has no conflict of interest directly relevant to the content of this review.

8.

9.

10.

11.

12.

13. 14.

15.

16.

17.

18.

19.

References 1. Sander JW, Shorvon SD. Epidemiology of the epilepsies. J Neurol Neurosurg Psychiatry 1996; 61: 433-43 2. Patsalos PN, Froscher W, Pisani F, et al. The importance of drug interactions in epilepsy therapy. Epilepsia 2002; 43: 365-85 3. Walker MC, Patsalos PN. Clinical pharmacokinetics of new antiepileptic drugs. Pharmacol Ther 1995; 67: 351-84 4. Patsalos PN. Pharmacokinetic profile of levetiracetam: toward ideal characteristics. Pharmacol Ther 2000; 85: 77-85 5. Patsalos PN. The new generation of anti-epileptic drugs. In: Bowman WC, Fitzgerald JD, Taylor JB, editors. Emerging drugs: the prospect for improved medicines. Vol. 4. London: Ashley Publications Ltd, 1999: 87-106 6. Cereghino J, Biton V, Abou-Khalil B, et al. Levetiracetam for partial seizures: results of a double-blind, randomized clinical trial. Neurology 2000; 55: 236-42 7. Betts T, Waegemans T, Crawford P. A multicentre, doubleblind, randomized, parallel group study to evaluate the tolerability and efficacy of two oral doses of levetiracetam, 2000mg

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20.

21.

22.

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Correspondence and offprints: Prof. Philip N. Patsalos, Pharmacology and Therapeutics Unit, Department of Clinical and Experimental Epilepsy, Institute of Neurology, Queen Square, London, WC1N 3BG, UK. E-mail: [email protected]

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