LEADING ARTICLE

Clin Pharmacokinet 2006; 45 (11): 1061-1075 0312-5963/06/0011-1061/$39.95/0 2006 Adis Data Information BV. All rights reserved.

Pharmacokinetic Variability of Newer Antiepileptic Drugs

When is Monitoring Needed?
Svein I. Johannessen1 and Torbj rn Tomson2 o
1 2 The National Center for Epilepsy, Sandvika, Norway Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden

Abstract

A new generation of antiepileptic drugs (AEDs) has reached the market in recent years with ten new compounds: felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, vigabatrin and zonisamide. The newer AEDs in general have more predictable pharmacokinetics than older AEDs such as phenytoin, carbamazepine and valproic acid (valproate sodium), which have a pronounced inter-individual variability in their pharmacokinetics and a narrow therapeutic range. For these older drugs it has been common practice to adjust the dosage to achieve a serum drug concentration within a predefined therapeutic range, representing an interval where most patients are expected to show an optimal response. However, such ranges must be interpreted with caution, since many patients are optimally treated when they have serum concentrations below or above the suggested range. It is often said that there is less need for therapeutic drug monitoring (TDM) with the newer AEDs, although this is partially based on the lack of documented correlation between serum concentration and drug effects. Nevertheless, TDM may be useful despite the shortcomings of existing therapeutic ranges, by utilisation of the concept of individual reference concentrations based on intra-individual comparisons of drug serum concentrations. With this concept, TDM may be indicated regardless of the existence or lack of a well-defined therapeutic range. The ten newer AEDs all have different pharmacological properties, and therefore, the usefulness of TDM for these drugs has to be assessed individually. For vigabatrin, a clear relationship between drug concentration and clinical effect cannot be expected because of its unique mode of action. Therefore, TDM of vigabatrin is mainly to check compliance. The mode of action of the other new AEDs would not preclude the applicability of TDM. For the prodrug oxcarbazepine, TDM is also useful, since the active metabolite licarbazepine is measured. For drugs that are eliminated renally completely unchanged (gabapentin, pregabalin and vigabatrin) or mainly unchanged (levetiracetam and topiramate), the pharmacokinetic variability is less pronounced and more predictable. However, the dose-dependent absorption of gabapentin increases its pharmacokinetic variability. Drug interactions can affect topiramate concentrations markedly, and individual factors such as age, pregnancy and renal function will contribute to the

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pharmacokinetic variability of all renally eliminated AEDs. For those of the newer AEDs that are metabolised (felbamate, lamotrigine, oxcarbazepine, tiagabine and zonisamide), pharmacokinetic variability is just as relevant as for many of the older AEDs. Therefore, TDM is likely to be useful in many clinical settings for the newer AEDs. The purpose of the present review is to discuss individually the potential value of TDM of these newer AEDs, with emphasis on pharmacokinetic variability.

Older antiepileptic drugs (AEDs), such as phenytoin, carbamazepine and valproic acid (valproate sodium), are characterised by a narrow therapeutic range and by a pronounced inter-individual variability in their pharmacokinetics.[1] Individualisation of dosage has therefore been a key concept in the efforts to optimise drug treatment of epilepsy, and in measuring drug concentrations in serum or plasma. Therapeutic drug monitoring (TDM), has become a frequently used tool in this effort. The utilisation of TDM varies markedly, but some commonly accepted general indications for TDM of the AEDs are: after initiation of treatment (to provide a baseline steady-state concentration); after change in drug dosage, in particular when non-linear pharmacokinetics apply (to confirm new drug concentration); at therapeutic failure (to confirm or exclude a pharmacokinetic explanation for uncontrolled seizures or adverse effects); to identify or control for drug-drug interactions; when pharmacokinetic alterations, due to physiological or pathological changes, are anticipated (e.g. pregnancy, hepatic disease, renal disease, gastrointestinal conditions potentially affecting drug absorption). These indications for TDM are relevant to most of the old and new AEDs, and are our recommendation. A new generation of AEDs has reached the market in recent years with ten new compounds: felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, vigabatrin and zonisamide, licensed in many countries since 1990. In general, new AEDs are often
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claimed to have a major advantage over the older AEDs in that they have more predictable pharmacokinetics and less need for TDM. The latter notion is to some extent also based on the lack of documented correlation between serum concentration and drug effects. The need for TDM is mainly related to the pharmacokinetic variability of an AED, but is also related to the nature of epilepsy and its treatment. Since the treatment is prophylactic, aiming at prevention of seizures without adverse drug effects, and because treatment failures may have serious consequences for the patient, dosage adjustments on clinical grounds alone are difficult. For the old generation AEDs it has been common practice to adjust the dosage to achieve a serum drug concentration within a predefined therapeutic range, a concentration interval at which the majority of patients are expected to show an optimal response. However, such ranges must be interpreted with a high degree of flexibility since many patients are best treated at serum concentrations below or above the suggested range.[2,3] Because the therapeutic ranges have been established based on studies of selected patients, their general applicability is limited by the fact that a number of factors can have an influence on the serum concentration required to produce an optimal drug response. However, TDM may be useful despite the shortcomings of existing therapeutic ranges, by utilisation of the concept of individual reference concentrations.[4] This strategy relies on intra-individual comparisons of drug serum concentrations. The drug concentration at which a patient has an optimal treatment effect is determined and will serve as the individual reference for comparison in case of future treatment failures.[4] This approach will help in unravelling the causes of a change in the
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clinical state of the patient, specifically to identify if such change is related to pharmacokinetic alterations or not. With the concept of the individual reference concentrations, TDM may be indicated, regardless of the existence of a well-defined therapeutic range. The usefulness of TDM will rather rely on: (i) the existence of a relationship between drug serum concentration and effect within the individual patient, which will depend on the mode of action of the drug and whether the effects are mediated through active metabolites; and (ii) whether there is an intra-individual variability in the pharmacokinetics, i.e. drug concentrations can be altered by intrinsic or external factors. The purpose of this review is to individually review each of the ten new AEDs with respect to properties of relevance for the usefulness of TDM, with emphasis on such pharmacokinetic variability. 1. Felbamate
1.1 Mechanism of Action

1.3 Pharmacokinetic Variability

Clearance of felbamate has been reported to be higher in children,[11] and slightly reduced in the elderly,[12] compared with younger adults. There are no data available on the pharmacokinetics of felbamate in infants or on the effect of pregnancy on felbamate serum concentrations. Renal impairment leads to higher serum concentrations of felbamate and extended t1/2 of 2734 hours, depending on the degree of renal dysfunction.[13] Felbamate is contradicted in patients with liver dysfunction. The metabolism of felbamate is enhanced by enzyme-inducing AEDs such as phenobarbital (phenobarbitone), phenytoin, primidone and carbamazepine, resulting in an average felbamate t1/2 of approximately 14 hours.[14,15] This interaction thus results in lower serum concentrations of felbamate.
1.4 Usefulness of Serum Concentration Monitoring

Felbamate is a dicarbamate derivative. The precise mechanism of action is unknown, but it inhibits seizures in mice that are induced by either N-methyl-D-aspartate (NMDA) or quisqualate, suggesting an anticonvulsant effect involving the NMDA receptor.[5]
1.2 Pharmacokinetics

After oral administration, felbamate is almost completely absorbed from the gastrointestinal tract, and peak serum concentrations are attained within 14 hours. The binding to serum proteins is only 30%. Felbamate is eliminated by renal excretion and oxidative metabolism, with formation of parahydroxy metabolites and 2-hydroxyl metabolites. Hydrolysis with formation of monocarbamoyl felbamate also takes place.[6-8] The intermediate metabolite, atropaldehyde, has been related to adverse idiosyncratic reaction of felbamate.[9,10] The elimination half-life (t1/2) is 1422 hours in adults when the drug is given as monotherapy.[7]
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Overall, although there is a lack of data from prospective studies, seizure control seems to be related to felbamate serum concentrations. Monitoring felbamate concentrations may be useful since felbamate appears to have a narrow therapeutic window, serum concentrations are not easily predicted from administered dosages, and felbamate concentrations are affected by age and comedication. TDM may be considered at steady state after initiation of treatment to provide an individual reference concentration, at therapeutic failure, and in conjunction with drug-drug interactions. In patients treated with therapeutic doses, serum felbamate concentrations in the 125250 mol/L range (3060 g/mL) have been reported.[16-19] 2. Gabapentin
2.1 Mechanism of Action

Gabapentin is a new chemical compound, designed as a structural analogue of GABA. In contrast with GABA, gabapentin readily penetrates the blood-brain barrier. In man, gabapentin has been demonstrated to increase GABA concentrations.[20]
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Most probably the mechanism of action is related to events modulated through its interaction with a receptor thought to be associated with the L-system amino acid carrier protein. However, the primary mechanism of action remains to be defined.[20,21]
2.2 Pharmacokinetics

2.4 Usefulness of Serum Concentration Monitoring

Gabapentin is rapidly absorbed from the gastrointestinal tract, and peak serum concentrations are attained 23 hours after a single dose. However, the bioavailability is reduced by up to 24% if certain antacids are taken concomitantly. The absolute bioavailability is at least 60%. Absorption kinetics are dose-dependent, possibly because of a saturable transport system. The drug is not bound to serum proteins. Gabapentin is not metabolised and is eliminated unchanged by the kidney. The t1/2 is about 57 hours after a single oral dose.[22-27]
2.3 Pharmacokinetic Variability

Because of its dose-dependent bioavailability, monitoring gabapentin may be justified after dose changes and in case of therapeutic failure. A wide range of gabapentin serum concentrations has been reported to be associated with seizure control.[18,30,31] However, no serum concentration controlled trials of gabapentin have been undertaken. In patients treated with therapeutic doses, serum gabapentin concentrations are in the order of 70120 mol/L (1220 g/mL).[18,19] 3. Lamotrigine
3.1 Mechanism of Action

In general, the concentration to dose ratio of gabapentin increases significantly with age.[28] Approximately 30% larger doses would be required in younger children (<5 years) to achieve the same exposure as in older children. The t1/2 is 59 hours in patients with normal renal function. Renal impairment reduces drug clearance and increases the serum concentration of gabapentin in a linear fashion. This is also of importance for elderly patients.[29] Since gabapentin is eliminated entirely by renal excretion, it could be a suitable alternative in patients with hepatic dysfunction. There are no data on the effect of pregnancy on gabapentin serum concentrations. Since it is not protein bound and is almost completely eliminated by renal excretion, gabapentin does not appear to be involved in significant pharmacokinetic interactions with other drugs. No significant interactions have been reported between gabapentin and other AEDs. However, cimetidine can cause a reduction in renal clearance of gabapentin, and antacids containing aluminium or magnesium can reduce gabapentin absorption by up to 20%.[29]
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Lamotrigine is a phenyltriazine derivative, unrelated to other currently available AEDs. Lamotrigine mainly acts via a use- and voltage-dependent blockade of neuronal voltage-activated sodium channels, and consequently inhibits the release of excitatory amino acids, especially glutamate.[32]
3.2 Pharmacokinetics

Lamotrigine displays linear pharmacokinetics. The drug is readily absorbed from the gastrointestinal tract, and peak serum concentrations are usually attained within 13 hours. The bioavailability of lamotrigine is virtually complete. The serum protein binding is about 55%.[33] Lamotrigine is metabolised mainly by glucuronidation, catalysed by uridine diphosphate-glucuronosyltransferase 1A4 primarily to N-2 glucuronide conjugate.[34] The t1/2 is 1530 hours in patients on monotherapy.[35]
3.3 Pharmacokinetic Variability

As expected for a drug that is eliminated by conjugation, there is age-dependent variability in lamotrigine pharmacokinetics. Hence, serum concentrations of lamotrigine decline slowly in breastfed newborns of mothers treated with lamotrigine.[36] Clearance in infants below the age of 2 months has also been reported to be significantly lower than in older infants.[37] On the other hand,
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clearance in children is up to 2-fold higher than in adults.[38-42] Clearance has been reported to be reduced by about 30% among healthy elderly adults, compared with middle aged adults.[43] Several studies have demonstrated pronounced alterations in the pharmacokinetics of lamotrigine during pregnancy.[36,44-46] Although individual differences exist, apparent clearance seems to increase steadily throughout pregnancy until peaking at approximately the 32nd gestational week. At this time a 330% increase from baseline has been observed.[46] Single dose pharmacokinetics has been assessed in patients with hepatic and renal dysfunction. Lamotrigine clearance was decreased and t1/2 increased in patients with liver cirrhosis. The change in lamotrigine pharmacokinetics correlated with the grade of cirrhosis with a median t1/2 of 110 hours in those with the most severe dysfunction.[34] Advanced renal failure is associated with a reduced clearance and increased lamotrigine t1/2 of approximately 50 hours.[47] Enzyme-inducing AEDs, such as phenobarbital, primidone, phenytoin and carbamazepine, enhance lamotrigine clearance leading to a shortened t1/2 (average 15 hours) and reduced steady-state concentrations, sometimes resulting in the need for dosage adjustments.[39,40] Oxcarbazepine, topiramate, as well as rifampicin (rifampin) can also induce the metabolism of lamotrigine. For oxcarbazepine a reduction of lamotrigine concentrations of 89% has been noted, for topiramate 4050%, and for riampicin about 50% reduction.[48-50] Likewise, oral contraceptives containing ethinylestradiol reduce steady-state concentrations of lamotrigine by 4065%.[51-53] The deinduction of lamotrigine metabolism is fairly rapid. As a consequence, lamotrigine plasma concentrations become 2-fold higher during the pill-free week with use of sequential oral contraceptives.[53] Valproic acid is a potent inhibitor of lamotrigine metabolism,[54,55] which can result in a 200% increase in circulating concentration and prolongation of the t1/2 to an average of 60 hours.[48] The antidepressant sertraline is another inhibitor producing a substantial increase (100%) in lamotrigine concentrations, and is associated with risk of toxicity.[56]
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3.4 Usefulness of Serum Concentration Monitoring

Similar to many old generation AEDs, lamotrigine exhibits pronounced pharmacokinetic variability, which can be further affected by age, pregnancy, concurrent diseases and drug-drug interactions. These characteristics of lamotrigine suggest that there is a clinical need to individualise patient therapy by the use of TDM. This is reasonable to consider at steady state after initiation of treatment to provide an individual reference concentration, at therapeutic failure, in conjunction with drug-drug interactions and at regular intervals during pregnancy. In most studies, a considerable overlap in the serum concentrations of lamotrigine between responders and non-responders, or between patients with or without adverse effects has been reported. Patients treated with therapeutic doses have serum lamotrigine concentrations in the order of 1060 mol/L (2.515 g/mL).[18,19] The incidence of toxicity rises steeply with concentrations above 60 mol/L,[57] but even higher concentrations seem to be tolerated in many patients.[58] 4. Levetiracetam
4.1 Mechanism of Action

Levetiracetam is the active, water-soluble Senantiomer of a racemic pyrrolidine acetamide and appears to act via the involvement of a novel binding site, the synaptic vesicle protein, SV2A.[59-61]
4.2 Pharmacokinetics

After oral administration, levetiracetam is completely absorbed and is not bound to serum proteins. Serum levetiracetam concentrations increase linearly with dose. The drug undergoes minimal metabolism (non-oxidative) to pharmacologically inactive metabolites and its excretion is primarily renal. In healthy volunteers, the time of maximum serum concentration of the drug is approximately 1 hour, and the t1/2 is 78 hours. The major metabolite accounts for one-quarter of the administered dose and
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has been found to be inactive; two-thirds is excreted unchanged in the urine.[62,63]

4.3 Pharmacokinetic Variability

5. Oxcarbazepine
5.1 Mechanism of Action

The elimination of levetiracetam is somewhat shorter in children (57 hours) and somewhat longer in the elderly (1011 hours). Children seem to have lower concentrations than adults on the same dose per bodyweight.[64] Preliminary data suggest that the elimination of levetiracetam is enhanced during pregnancy.[65] Clearance of levetiracetam is decreased in patients with renal impairment and is correlated with creatinine clearance. Patients with mild to moderate hepatic dysfunction show no significant alterations in levetiracetam clearance. Patients with severe liver impairment have been found to exhibit a reduction in clearance by about 50%, but these patients showed a concomitant decrease in renal function, which accounted for a decreased excretion of the drug.[66] Therefore, no alterations in dosage requirements are expected in liver disease, unless renal function is simultaneously impaired. Levetiracetam is unlikely to be involved in clinically important interactions by induction or inhibition of cytochrome P450 (CYP) reactions. Newer data show that enzyme-inducing AEDs may moderately lower levetiracetam serum concentrations.[64,67]
4.4 Usefulness of Serum Concentration Monitoring

Oxcarbazepine is the keto-derivative of carbamazepine. It was developed by introducing minimal changes in the structure of carbamazepine, which altered the metabolism to avoid the production of the epoxide metabolite. At least part of the anticonvulsant effect of oxcarbazepine is based on interactions with sodium and potassium channels. In addition, the monohydroxy metabolite, 10,11-dihydro10-hydroxy-carbamazepine (MHD, licarbazepine), the active entity following oxcarbazepine oral dosing, reduces voltage-activated calcium currents in striatal and cortical neurons.[68-71]
5.2 Pharmacokinetics

The relationship between levetiracetam serum concentrations and clinical effect has not been ascertained and consequently, the value of serum concentration measurements has not been established. However, there may well be potential useful applications of drug monitoring of levetiracetam, for example during pregnancy or for ascertaining compliance, although the pharmacokinetic variability of levetiracetam seems less pronounced than for some other AEDs. In patients treated with therapeutic doses, serum levetiracetam concentrations in the 35120 mol/L range (826 g/mL) have been reported.[18,19]
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Oxcarbazepine is a prochiral prodrug, which is rapidly and almost completely metabolised to licarbazepine. Licarbazepine has independent anticonvulsant properties and is mainly responsible for the effects of oxcarbazepine. Peak serum concentrations of this metabolite are attained at about 8 hours, and the protein binding is about 40%. Oxcarbazepine is extensively metabolised to two pharmacologically active, equipotent enantiomers of licarbazepine. This biotransformation of oxcarbazepine is highly stereoselective, with a 5-fold difference between the area under the concentrationtime curves (AUC) of the two licarbazepine enantiomers.[72,73] The t1/2 of both enantiomers is in the order of 810 hours.[74-76] Oxcarbazepine and its major active metabolite are cleared from the human body mainly by non-oxidative processes independent of the CYP system and the pharmacokinetics are linear. In contrast to carbamazepine, oxcarbazepine does not induce its own metabolism after repeated administration.[76]
5.3 Pharmacokinetic Variability

There is no information on the pharmacokinetics of oxcarbazepine in infants. Children aged 26 years have a higher clearance of licarbazepine and require a larger dose/kg bodyweight of oxcarbazepine, comClin Pharmacokinet 2006; 45 (11)

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pared with older children and adults, to obtain an effective serum concentration.[77,78] Clearance may be more than twice as high compared with adults. In contrast, clearance of licarbazepine is reduced by approximately 30% in elderly patients.[79] Data based on five pregnancies suggest pronounced gestational related changes in the pharmacokinetics of oxcarbazepine, with decline in licarbazepine serum concentrations by more than 50% in late pregnancy.[80] The clearance of both oxcarbazepine and licarbazepine is reduced in patients with impaired renal function, with approximately 50% reduction in patients with pronounced renal dysfunction.[81] Enzyme-inducing AEDs, phenytoin, phenobarbital and carbamazepine, enhance the metabolism of licarbazepine, and plasma concentrations of licarbazepine are reduced by 2040%.[82-84] NonAEDs that affect the pharmacokinetics of carbamazepine, such as erythromycin and dextropropoxyphene, appear to have no influence on licarbazepine serum concentrations[85-87].
5.4 Usefulness of Serum Concentration Monitoring

6. Pregabalin
6.1 Mechanism of Action

Pregabalin, like gabapentin, is designed as a structural analogue of GABA. The putative mechanism of action of pregabalin is reduced excitatory neurotransmitter release caused by binding to voltage-gated calcium channel alpha (2)-delta subunits, resulting in allosteric modulation of P/Q-type channels. Pregabalin has no effects on GABAergic mechanisms.[91,92]
6.2 Pharmacokinetics

Absorption of pregabalin is extensive, rapid and proportional to dose. Maximum serum concentration is achieved approximately 1 hour after oral administration and is dose-proportional. Food intake has no clinically relevant effect on the amount of pregabalin absorbed. The mean t1/2 is 6.3 hours. Pregabalin does not bind to serum proteins and is excreted virtually unchanged by the kidneys (<2% metabolism).[91,92]
6.3 Pharmacokinetic Variability

While less pronounced than for carbamazepine, oxcarbazepine has a considerable pharmacokinetic variability, which can also be affected by age, pregnancy, concurrent diseases and drug-drug interactions. These characteristics suggest that TDM may be of value in treatment with oxcarbazepine. TDM may be considered at steady-state after the initiation of treatment (to provide an individual reference concentration), at therapeutic failure, in conjunction with drug-drug interactions, and during pregnancy. The therapeutic range of serum concentrations for the active metabolite of oxcarbazepine, licarbazepine, has not yet been well defined. Similar concentrations have been noted in groups of patients with optimal treatment and in non-responders.[88-90] In patients treated with therapeutic doses of oxcarbazepine, serum concentrations of licarbazepine are in the 50140 mol/L (1235 g/mL) range.[18,19]
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There are no data on the effect of age or pregnancy on pregabalin serum concentrations. Pregabalin is not subject to hepatic metabolism and does not induce or inhibit liver enzymes. Therefore, pregabalin is unlikely to be involved in pharmacokinetic drug-drug interactions. However, dosage adjustment may be necessary in patients with renal insufficiency.[91,92] Since pregabalin is primarily eliminated by renal excretion it could be an alternative for patients with hepatic dysfunction.
6.4 Usefulness of Serum Concentration Monitoring

The available data and the fact that pregabalin is eliminated renally suggest comparatively small variability in pharmacokinetics and thus a limited value of TDM. Data on TDM for pregabalin are also scarce. Recently, Berry and Millington[93] reported on concentration measurements in predose trough concentration samples from a group of patients with
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doses escalated up to a maximum of 600mg daily and found a concentration range of 1852 mol/L (2.88.2 g/mL) at steady state. 7. Tiagabine
7.1 Mechanism of Action

which is of possible importance for interpretation of TDM data. Other highly protein-bound drugs, such as naproxen and salicylates, displace tiagabine from its protein binding sites, leading to slightly decreased total serum concentrations.[99] The t1/2 is shortened and the serum concentrations are lowered in patients also treated with enzyme-inducing AEDs.[100]
7.4 Usefulness of Serum Concentration Monitoring

Tiagabine, which consists of nipecotic acid linked by an aliphatic chain to a lipophilic anchor, is structurally different from other AEDs. Its mode of action seems to be mediated by inhibition of GABA reuptake from the synaptic cleft. The lipophilic portion of the tiagabine molecule permits penetration across the blood-brain barrier. Tiagabine is a potent AED in several rodent models.[94]
7.2 Pharmacokinetics

After oral administration, the absorption of tiagabine is very rapid with peak serum concentrations attained between 0.5 and 2 hours. Coadministration with a meal is recommended to minimise potentially excessive peak serum concentrations and to reduce fluctuations between doses. The protein binding is very high (96%). The t1/2 is quite variable, ranging from 4 to 13 hours with an average of about 7 hours. Tiagabine is extensively metabolised. There is no evidence of dose-dependent pharmacokinetics.[95]
7.3 Pharmacokinetic Variability

Although the relationship between dose and serum concentration is linear, there are large intraindividual and inter-individual variations in serum concentration. There are also large inter-dose fluctuations in serum concentration (attributable to the short t1/2 of tiagabine). However, information on the concentration-effect relations with tiagabine is scarce, and difficulties with measuring its low serum concentrations have resulted in poor analytical reliability in some laboratories.[101] In one study,[102] trough concentrations >96 nmol/L (>40 ng/mL) were reported to be associated with the greatest reduction in seizure frequency. In patients treated with therapeutic doses, serum tiagabine concentrations are in the order of 50250 nmol/L (20100 ng/ mL).[18,19,102,103] 8. Topiramate

Clearance of tiagabine is higher in children than in adults.[96] There are no data on the effect of pregnancy on tiagabine serum concentrations, but tiagabine is the only newer AED that is highly protein bound and thus potentially subject to significant alterations in free fraction during pregnancy.[97] The pharmacokinetics of tiagabine are unaffected in subjects with renal failure. Patients with impaired liver function may require reduced initial and maintenance doses of tiagabine and/or longer dose administration intervals, compared with patients with normal hepatic function. Hepatic dysfunction prolongs the half-life to 1216 hours.[98] Valproic acid displaces tiagabine from its binding sites on serum proteins in a concentration-dependent manner,
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8.1 Mechanism of Action

Topiramate is a sulfamate-substituted monosaccharide. The drug has multiple mechanisms of action including modulation of voltage-dependent sodium channels; potentiation of GABAergic inhibition at a novel site on the GABAA receptor, and a possible action at non-NMDA receptors. The drug is also a weak inhibitor of carbonic anhydrase, which is unlikely to contribute to its antiepileptic effects.[104]
8.2 Pharmacokinetics

After oral administration of topiramate the bioavailability is almost complete. The absorption is
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rapid, and peak serum concentrations are attained within 14 hours. Topiramate is only 15% bound to serum proteins. In healthy volunteers, topiramate is not extensively metabolised, being eliminated mainly unchanged via the kidneys. The serum t1/2 is 2030 hours.[104]
8.3 Pharmacokinetic Variability

tion, at therapeutic failure, and in conjunction with drug-drug interactions. 9. Vigabatrin

9.1 Mechanism of Action

A wide scatter of serum topiramate concentrations versus dose (mg/kg bodyweight) has been observed. Serum concentrations of topiramate for the same mg/kg dose are about 30% lower in children than in adults. Children (<11 years) require much higher doses in mg/kg bodyweight to achieve drug concentrations comparable to those observed in young adults.[105-109] There are no data on the effect of pregnancy on topiramate serum concentrations. The dose of topiramate should be reduced by 50% in patients with a creatinine clearance <70 mL/minute.[110] In hepatically impaired patients, topiramate should be administered with caution as the clearance of topiramate may be decreased. Enzyme-inducing AEDs can reduce the serum concentrations of topiramate by approximately 50%.[106] Although valproic acid is reported to lower topiramate concentrations by 1015%, this is unlikely to be of clinical significance.[111]
8.4 Usefulness of Serum Concentration Monitoring

Vigabatrin is a synthetic GABA derivative. It is an enzyme-activated, irreversible inhibitor of GABA transaminase that resulted from a systematic search into possible ways of increasing GABAergic inhibition through interference with GABA metabolism. The drug is a racemic mixture, although only the S-(+)-enantiomer being pharmacologically active.[117,118]
9.2 Pharmacokinetics

After oral administration of vigabatrin, peak serum concentrations are attained within about 2 hours. Vigabatrin enters the cerebrospinal fluid (CSF) and produces dose-dependent increases in GABA concentrations in CSF. Vigabatrin is not bound to serum proteins, and no metabolites have been identified in humans. The t1/2 is between 5 and 8 hours. Because of the irreversible mode of action of the drug, the t1/2 bears almost no relationship to the duration of pharmacological effect. Because of the long-lasting GABA transaminase inhibition, the anticonvulsant effect of vigabatrin long outlasts its presence in serum.[119]
9.3 Pharmacokinetic Variability

There is a linear relationship between topiramate dose and serum concentration in both adults and children,[105] and a wide range of doses and serum concentrations of topiramate has been associated with optimal clinical response.[112-115] In patients treated with therapeutic doses, serum topiramate concentrations in the order of 1560 mol/L (520 g/mL) have been reported, even though most patients will probably have concentrations in the lowto-mid range with the dosage regimens currently used.[18,19,114-116] Because of its reported pharmacokinetic variability, monitoring topiramate may be considered at steady state after initiation of treatment to provide an individual reference concentra 2006 Adis Data Information BV. All rights reserved.

Children have a higher clearance of vigabatrin compared with adults, and therefore require higher doses in mg/kg to attain comparable serum concentrations.[120] There are no data on the effect of pregnancy on vigabatrin serum concentrations. Vigabatrin is excreted unchanged primarily in the urine, and thus, patients with renal impairment are likely to require lower doses.[119] It is unlikely that vigabatrin pharmacokinetics are influenced by hepatic dysfunction. No drug interactions have been observed between vigabatrin and other AEDs or other drug classes, except for a decrease in serum phenytoin
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concentrations in some patients, which was of no clinical significance.[121]

9.4 Usefulness of Serum Concentration Monitoring

10.3 Pharmacokinetic Variability

In contrast to most other AEDs, the monitoring of serum concentrations of vigabatrin is not suitable as a guide to therapy because of its mechanism of action. Since vigabatrin acts by irreversible inhibition of the enzyme GABA transaminase, there is a clear dissociation between its concentration profile in serum and the duration of pharmacological effect; the effect being related to the regeneration time of the enzyme. However, serum vigabatrin concentrations as a check on recent compliance may be useful.[18] 10. Zonisamide
10.1 Mechanism of Action

As for other AEDs, children require higher doses in mg/kg to attain serum concentrations of zonisamide of the same order as in adults. The serum concentration to dose ratio increases with age.[127] There are no data on the effect of pregnancy on zonisamide serum concentrations. Because zonisamide is metabolised in the liver and excreted by the kidneys, patients with renal or hepatic disease should be treated with caution, and might require slower titration and more frequent monitoring. The t1/2 is reduced to 2535 hours in patients comedicated with enzyme-inducing AEDs.[125,128] In contrast, serum zonisamide concentrations decrease only slightly when valproic acid is coadministered. The pharmacokinetics of zonisamide and lamotrigine are not affected when these two drugs are coadministered.[129]
10.4 Usefulness of Serum Concentration Monitoring

Zonisamide, a benzisoxazole sulphonamide, is a relatively weak inhibitor of carbonic anhydrase. It prevents repetitive neuronal firing by blocking voltage-sensitive Na+ channels and also reduces voltage-dependent T-type Ca2+ channels, facilitates dopaminergic and serotoninergic neurotransmission, and may protect neurons from free-radical damage, thereby stabilising neuronal membranes.[122-124]
10.2 Pharmacokinetics

Zonisamide is well absorbed from the gastrointestinal tract, and peak serum concentrations are attained within 47 hours after oral intake. The drug extensively accumulates in erythrocytes. The serum protein binding is about 60%, which decreases with increasing serum concentrations when the drug is given in therapeutic doses. Zonisamide otherwise exhibits linear pharmacokinetics up to daily doses of 1015 mg/kg and is extensively metabolised by acetylation, followed by conjugation with glucuronic acid. The t1/2 is 5070 hours in patients receiving monotherapy.[125,126]
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No clear relationship between zonisamide serum concentrations and clinical response has yet been established, and there is considerable overlap of serum concentrations between seizure-free patients and non-responders, as well as those associated with seizure control and adverse effects.[130] A range of 45180 mol/L (1038 g/mL) has been reported in patients treated with therapeutic doses.[18,19] As a result of the reported pharmacokinetic variability, the TDM of zonisamide may be considered at steady state after initiation of treatment to provide an individual reference concentration, at therapeutic failure, and in conjunction with drug-drug interactions. 11. Conclusions The ten new generation AEDs all have different pharmacological properties and the applicability of TDM in the use of these agents has to be assessed for each drug individually. Data of relevance for TDM of the new drugs are summarised in table I. As with older AEDs, therapeutic ranges are poorly defined if at all properly studied. Those quoted in table I should thus be applied with considerable flexibiliClin Pharmacokinet 2006; 45 (11)

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Table I. Some pharmacokinetic characteristics of newer antiepileptic drugs Drug Felbamate Gabapentin Lamotrigine Levetiracetam Oxcarbazepine Pregabalin Tiagabine Topiramate Vigabatrin Zonisamide a b c d Time to steady state (d) 35 2 315 2 23 2 2 46 12 512 Half-life (h) 1422 57 833 78 815 67 79 2030 58 5070 Tentative therapeutic rangea (mol/L) 125250 70120 1060 35120 50140b NE 50250c 1560 NA 45180 (g/mL) 3060 1220 2.515 826 1235 2.88.2 20100d 520 NA 1038 Oxidation and renal excretion Renal excretion Glucuronide conjugation Renal excretion and hydrolysis Keto-reduction, then glucuronide conjugation of MHD Renal excretion Oxidation Renal excretion, oxidation Renal excretion Glucuronide conjugation, acetylation, oxidation and renal excretion Major route of elimination

The lower limit of the therapeutic range is of limited value, because many patients do well at serum concentrations below this limit. Monohydroxy derivative. nmol/L. ng/mL.

MHD = monohydroxy metabolite; NA = not applicable; NE = not established.

ty. Although TDM can be based on the individual reference concentration rather than general therapeutic ranges, this concept builds on the existence of a within-patient relationship between drug serum concentration and clinical effects. Because of its unique mode of action, a clear relationship of this kind cannot be expected for vigabatrin. Therefore, indications for TDM of vigabatrin are limited mainly to checking compliance. Current knowledge about the mode of action of the other new AEDs would not preclude the applicability of TDM. Additionally, the fact that oxcarbazepine is a prodrug does not limit the usefulness of TDM, since the active licarbazepine metabolite is measured. Pharmacokinetic variability is less pronounced and more predictable for drugs that are eliminated completely (gabapentin, pregabalin and vigabatrin) or predominantly (levetiractem and topiramate) unchanged through the kidneys. However, the dosedependent absorption of gabapentin increases its pharmacokinetic variability. Comedication can affect topiramate concentrations markedly, as can other AEDs that are metabolised, and individual factors, such as age, pregnancy and renal function contribute to the pharmacokinetic variability of all renally eliminated AEDs. Of the new generation
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AEDs that are cleared by metabolism (felbamate, lamotrigine, oxcarbazepine, tiagabine and zonisamide), pharmacokinetic variability is just as relevant as for many of the traditional AEDs. TDM is therefore likely to be useful in many clinical settings with the arrival of the new generation AEDs. Acknowledgements
No sources of funding were used to assist in the preparation of this manuscript. The authors have no conflict of interests that are directly relevant to the content of this manuscript.

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Correspondence and offprints: Dr Svein I. Johannessen, The National Center for Epilepsy, Sandvika, POB 56, N-1306 Brum postterminal, Norway. E-mail: Svein.Johannessen@epilepsy.no

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