Interactions between antiepileptic drugs

Review

Clinically important drug interactions in epilepsy: general features and interactions between antiepileptic drugs

Philip N Patsalos and Emilio Perucca

There are two types of interactions between drugs, pharmacokinetic and pharmacodynamic. For antiepileptic drugs (AEDs), pharmacokinetic interactions are the most notable type, but pharmacodynamic interactions involving reciprocal potentiation of pharmacological effects at the site of action are also important. By far the most important pharmacokinetic interactions are those involving cytochrome P450 isoenzymes in hepatic metabolism. Among old generation AEDs, carbamazepine, phenytoin, phenobarbital, and primidone induce the activity of several enzymes involved in drug metabolism, leading to decreased plasma concentration and reduced pharmacological effect of drugs, which are substrates of the same enzymes (eg, tiagabine, valproic acid, lamotrigine, and topiramate). In contrast, the new AEDs gabapentin, lamotrigine, levetiracetam, tiagabine, topiramate, vigabatrin, and zonisamide do not induce the metabolism of other AEDs. Interactions involving enzyme inhibition include the increase in plasma concentrations of lamotrigine and phenobarbital caused by valproic acid. Among AEDs, the least potential interaction is associated with gabapentin and levetiracetam.

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Up to 70% of patients diagnosed with epilepsy can be made seizure-free by currently available antiepileptic drugs (AEDs) given as monotherapy. In patients who are unresponsive to monotherapy, however, a combination of two or more AEDs may be needed to optimise seizure control. However, combination therapy may have adverse effects.1 When two or more AEDs are used, the potential for drug interactions is substantial, and such interactions may have a profound effect on patients’ wellbeing.2,3

In this review we summarise the main mechanisms of drug interactions, highlight the most important interactions between AEDs, and provide guidelines on how to anticipate, prevent, and detect adverse interactions between AEDs. Interactions between AEDs and drugs prescribed for the management of other disorders will be discussed in part two of this article, which will appear in a future issue of The Lancet Neurology.

Mechanisms of drug interaction

There are two basic types of drug interactions, pharmacokinetic and pharmacodynamic.2,4 Pharmacokinetic interactions involve a change in the absorption, distribution, or elimination of the affected drug and account for most of the interactions reported to date because they are easily identifiable by a change in drug concentrations in the

plasma. Pharmacodynamic interactions, although also important, are less well recognised and are commonly inferred to explain apparently drug-induced changes in clinical status that cannot be attributed to a pharmacokinetic mechanism.5

Pharmacokinetic interactions

Effects on drug absorption

Although, AED interactions affecting gastrointestinal absorption are rare, such interactions can be important in some cases; one example is impaired phenytoin absorption, which is seen when the drug is given together with certain nasogastric feeds.3–8 Phenytoin is thought to bind to constituents of the feeding formulas to form insoluble complexes that cannot be absorbed.

Transporters, particularly P-glycoprotein, may play an important part in the gastrointestinal absorption of many drugs,9 including digoxin,10 ciclosporin,11,12 paclitaxel,13 and docetaxel.14 There is evidence that P-glycoprotein is involved in mediating the efflux of some AEDs, including carbamazepine,15,16 phenytoin,16,17 phenobarbital,18 lamo- trigine,18 and felbamate18 across the blood–brain barrier. Overexpression of P-glycoprotein in brain tissue may limit the penetration of AEDs to their sites of action and is being investigated as a potential mechanism of pharmaco- resistance in epilepsy.19 Whether P-glycoprotein also plays an important part in the gastrointestinal absorption of AEDs is, however, unknown. The distribution of P-glycoprotein varies substantially across the gastrointestinal tract, and its role and contribution to drug absorption may differ among drugs.20 Moreover, the expression of P-glycoprotein in the gut, and in other tissues, can be induced and inhibited by other drugs, many of which are also inducers and inhibitors of the cytochrome P450 (CYP) isoenzyme CYP3A4.21–24 On the basis of these observations, some AED interactions that are currently ascribed to other mechanisms could be mediated by modulation of P-glycoprotein function at the level of drug absorption or distribution, although this possibility has not been investigated.

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PNP is at the Department of Clinical and Experimental Epilepsy, Institute of Neurology, University College London, London, UK, and EP is at the Clinical Pharmacology Unit, Department of Internal Medicine and Therapeutics, University of Pavia, Pavia, Italy.

Correspondence: Dr Philip N Patsalos, Pharmacology and Therapeutics Unit, Department of Clinical and Experimental Epilepsy, Institute of Neurology, Queen Square, London, WC1N 3BG, United Kingdom. Tel +44 (0)20 7837 3611 ext 3830;

fax +44 (0)20 7278 5616; email p.patsalos@ion.ucl.ac.uk

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Review

Interactions between antiepileptic drugs

Displacement from plasma proteins

Interactions affecting drug distribution may involve competition between two drugs for binding sites on plasma proteins. In quantitative terms, these interactions can be important only for drugs that are over 90% bound to plasma proteins and, among AEDs, only phenytoin, valproic acid, diazepam, and tiagabine belong to this category.25 Although diazepam and tiagabine can be displaced from plasma proteins by concurrently given highly protein-bound drugs, they are present in the circulation at nanomolar concentrations and they would not be expected to displace—to a substantial extent—compounds with therapeutic concentrations in the micromolar range.26

The implications of plasma-protein displacement interactions are frequently misunderstood. Only the unbound (free) fraction is in equilibrium with the receptor sites, and only this fraction has pharmacological effects. The amount of drug that is displaced from plasma proteins is generally a tiny fraction of the total amount of drug present in the body and is therefore insufficient to produce a change in clinical response.27,28 As a rule, displacement from plasma proteins results in a fall in total drug concentration (as the displaced drug redistributes rapidly into tissues and undergoes compensatory elimination), but the concentration of free drug and magnitude of the pharmacological effect are practically unchanged. Plasma- protein binding interactions are clinically relevant for only a few drugs with exceptional pharmacokinetic characteristics and none of the available AEDs.29 Nevertheless, awareness of these interactions is important for interpretation of plasma drug concentration measurements in clinical practice. In fact, in the presence of a plasma-protein binding interaction, therapeutic and toxic effects will occur at low total drug concentrations; patient management may benefit from the monitoring of free (unbound) drug concentrations.30,31

The most commonly occurring plasma-protein displacement interaction involving AEDs is the displacement of phenytoin by valproic acid:32,33 typically, this interaction results in a fall in total phenytoin concentration although the concentration of free—pharmacologically active— phenytoin does not change.34 In some patients, a small rise in the concentration of free phenytoin may be seen owing to inhibition of phenytoin metabolism by valproic acid,35 or a transient displacement of phenytoin from tissue binding sites.36 This rise may be associated with signs of phenytoin toxicity. The most important implication of this interaction, however, is that in the presence of valproic acid the “therapeutic” range of total plasma phenytoin concentrations is shifted towards lower values. The clinical significance of a recently reported in vitro concentration- dependent displacement of tiagabine by valproic acid is unknown.37

Metabolic drug interactions

By far the most important pharmacokinetic interactions with AEDs are those related to induction or inhibition of drug metabolism.38,39

Enzyme induction, which is caused mainly by carbamazepine, phenytoin, and barbiturates (ie, pheno-

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barbital and primidone), is increased synthesis of drug- metabolising isoenzymes in the liver40 and in other tissues.41 The increase in enzyme activity results in an increase in the rate of metabolism of drugs that are substrates of those enzymes, and thus, the plasma concentration of those drugs is decreased. If the affected drug has an active metabolite, induction can result in increased metabolite concentration and possibly an increase in drug toxicity. As enzyme induction requires synthesis of new enzymes, the time course of induction (and its reversal upon removal of the inducer) is dependent on the rate of enzyme synthesis and degradation and the time to reach steady-state concentrations of the inducing drug. Thus, the time course of induction is generally gradual and dose-dependent.40,42,43

Enzyme inhibition is the phenomenon by which a drug or its metabolite blocks the activity of one or more drug- metabolising enzymes, which results in a decrease in the rate of metabolism of the affected drug. This, in turn, will lead to high plasma concentrations of the drug and, possibly, clinical toxicity. Inhibition is normally competitive and dose-dependent, and begins as soon as sufficient concentrations of the inhibitor are achieved. Substantial inhibition is seen within 24 h of the inhibitor being given in many cases.38,39

In recent years, characterisation of the isoenzymes involved in the metabolism of individual drugs has greatly improved the prediction of metabolic interactions.26,38,39 At the level of CYP, four isoenzymes (CYP3A4, CYP2D6, CYP2C9, and CYP1A2) are known to have a role in the metabolism of 95% of all drugs, and 50–70% of all drugs might be substrates of CYP3A4.44 Three isoenzymes (CYP2C9, CYP2C19, and CYP3A4) are of particular importance in relation to AED interactions. Databases of substrates, inhibitors, and inducers of different CYP isoenzymes provide an invaluable resource in helping to anticipate potential interactions (table 1). For example, knowledge that carbamazepine is an inducer of CYP3A4 suggests that it will reduce the plasma concentration of CYP3A4 substrates such as ethosuximide, tiagabine, steroid oral contraceptives, and dihydropyridine calcium antagonists.2 Likewise, the ability of erythromycin to inhibit CYP3A4 explains the clinically important rise in plasma carbamazepine concentration.2

Uridine glucuronyl transferases (UGTs) catalyse glucuronidation; there are two distinct families, UGT1 and UGT2, with eight isoenzymes identified in each. The UGT1A4 isoenzyme plays an important part in the glucuronidation of lamotrigine,45 whereas the isoenzyme isoforms that catalyse the glucuronide conjugation of valproic acid have not yet been identified. Like CYP- mediated reactions, glucuronidation is susceptible to inhibition and induction.

Effects on renal excretion

Drugs that undergo extensive renal elimination in unchanged form may be susceptible to interactions affecting the excretion process, particularly when it involves active transport mechanisms or when the ionised state of the drug is highly sensitive to changes in urine pH.46 Agents that cause

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Interactions between antiepileptic drugs

Review

alkalinisation of urine increase the elimination of phenobarbital by reducing the reabsorption of this acidic drug from the renal tubuli,47 an effect that can be exploited therapeutically in severe cases of barbiturate intoxication. There are no other examples of major AED interactions involving changes in renal excretion.

Pharmacodynamic interactions

Pharmacodynamic interactions take place directly at the site of action and result in a modification of pharmacological effect without any change in drug concentrations in the

plasma. The effects of the interacting drugs can be additive (when they equal the sum of the effects of the individual drugs), synergistic (when the combined effects are greater than expected from the sum of individual effects), or antagonistic (when the combined effects are less than additive).48 Pharmacodynamic interactions can be adverse (when the increase in toxicity is greater than any gain in anticonvulsant activity) or beneficial (when therapeutic effects are additive or synergistic, and toxic effects are less than additive). To some extent, these interactions can be explained through knowledge of the mechanisms of action

Table 1. Substrates, inhibitors, and inducers of the major (CYP) isoenzymes involved in drug metabolism*

Isoenzymes Substrates

Inhibitors

Ciprofloxacin Clarithromycin Fluvoxamine Furafylline

Valproic acid Amiodarone Chloramphenicol Fluconazole Fluoxetine Fluvoxamine Miconazole Sulfaphenazole

Felbamate Oxcarbazepine (weak) Topiramate (weak) Cimetidine Fluvoxamine Omeprazole Ticlopidine

Cimetidine Fluoxetine Haloperidol Paroxetine Perphenazine Propafenone Quinidine Thioridazine

Disulfiram

Cimetidine Ciclosporin A Diltiazem Erythromycin Fluconazole Fluvoxamine Grapefruit juice Indinavir

Itraconazole Ketoconazole Nefazodone Dextropropoxyphene Ritonavir Troleandomycin Verapamil

Inducers

Carbamazepine Phenobarbital Phenytoin

Primidone

Cigarette smoke Charcoal-grilled meat Rifampicin

Carbamazepine Phenobarbital Phenytoin Primidone Rifampicin

Carbamazepine Phenobarbital Phenytoin Primidone Rifampicin

No inducer known

Alcohol Isoniazid

Carbamazepine Phenobarbital Phenytoin Primidone Oxcarbazepine† Topiramate† Felbamate† Glucocorticoids† St John’s Wort Rifabutin Rifampicin

CYP1A2

CYP2C9

CYP2C19

CYP2D6

CYP2E1 CYP3A4

Psychotropic drugs: amitriptyline, clozapine, clomipramine, fluvoxamine, haloperidol, imipramine, mirtazapine, olanzapine Miscellaneous: caffeine, theophylline,

paracetamol, tacrine, tamoxifen, R-warfarin

AEDs: phenobarbital, phenytoin, valproic acid

Non-steroidal anti-inflammatory drugs: celecoxib, diclofenac, ibuprofen, naproxen, piroxicam

Miscellaneous: fluvastatin, losartan, tolbutamide, torasemide, S-warfarin, zidovudine

AEDs: diazepam, S-mephenytoin, methylphenobarbital, phenytoin Psychotropic drugs: amitriptyline, clomipramine, imipramine, citalopram, moclobemide

Miscellaneous: omeprazole, propranolol, proguanil, R-warfarin

Psychotropic drugs: amitriptyline, citalopram, chlorpromazine, clomipramine, clozapine, imipramine, desipramine, fluoxetine, fluphenazine, fluvoxamine, haloperidol, mianserine, mirtazapine, nortriptyline, olanzapine, paroxetine, perphenazine, risperidone, thioridazine, venlafaxine, zuclopenthixol

Cardiovascular drugs: alprenolol, bufuralol, encainide, flecainide, metoprolol, propafenone, propranolol, timolol, pindolol Miscellaneous: codeine, debrisoquine, dextromethorphan, phenformin, tramadol

AEDs: felbamate, phenobarbital

Miscellaneous: dapsone, ethanol, halothane, isoniazid, chlorzoxazone

AEDs: carbamazepine, ethosuximide, tiagabine, zonisamide,

some benzodiazepines (eg, alprazolam, midazolam, triazolam) Psychotropic drugs: amitriptyline, clomipramine, clozapine, haloperidol, imipramine, sertraline, nefazodone, mirtazapine, risperidone, ziprasidone, olanzapine

Cardiovascular drugs: amiodarone, atorvastatin, diltiazem, felodipine, lovastatin, nimodipine, nifedipine, quinidine, simvastatin, verapamil Miscellaneous: alfentanil, astemizole, cisapride, clarithromycin, ciclosporin A, cyclophosphamide, erythromycin, fentanyl, glucocorticoids, itraconazole, ketoconazole, indinavir,

oral contraceptive steroids, sildenafil, tacrolimus, tamoxifen, terfenadine

*The list is intended for guidance only and should not be regarded as exhaustive. Prediction of drug interactions based on this table should be with caution, because enzyme induction and inhibition may coexist and because many other factors (Panel) are involved in determining whether a clinically significant drug interaction will or will not occur. †These inducers are weaker or may induce CYP3A4 isoenzymes only in certain tissues.

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Review

Interactions between antiepileptic drugs

Factors important to the clinical implications of a

potential metabolic interaction

The nature of the interaction at the enzyme site

Is it a substrate, an inhibitor or an inducer?

The spectrum of isoenzymes that are induced or inhibited by the interacting agent

The potency of the inhibition/induction

A potent effect will result in a more ubiquitous interaction affecting many/most patients.

The concentration of the inhibitor/inducer at the isoenzyme site

Drugs that achieve low concentrations in blood may never reach the concentration threshold necessary to elicit an interaction.

The extent of metabolism of the substrate through the particular isoenzyme

If the affected enzyme causes only a small proportion of the drug’s clearance, inhibition will not result in a substantial interaction.

However, a very large increase in the activity of the affected enzyme could substantially affect the total clearance of the drug.

The saturability of the isoenzyme

Isoenzymes that are saturable at drug concentrations encountered clinically are more susceptible to significant inhibitory interactions.

The route of administration

For drugs showing extensive first-pass metabolism, any change in the plasma concentration of the drug caused by enzyme induction or inhibition will be much greater after oral than after parenteral administration.

The presence of pharmacologically active metabolites

Such metabolites complicate the outcome of a potential interaction as they may be enzyme inducers or inhibitors.

The therapeutic window of the substrate

Interactions affecting drugs with a narrow therapeutic window are more likely to be of clinical significance.

The concentration of the affected drug at baseline

Any change in plasma drug concentration will have important effects if the baseline concentration is near the threshold of toxicity or near the threshold required to produce a desirable therapeutic effect.

The genetic predisposition of the individual patient

Patients with deficiency of a genetically polymorphic isoenzyme (eg, CYP2D6 or CYP2C19) will not have interactions mediated by induction or inhibition of that isoenzyme.

The susceptibility and the sensitivity of the individual in relation to adverse effects

Elderly patients are more susceptible to interactions because they are more likely to receive multiple medications and are more sensitive to the adverse effects of drugs.

The probability of the potential interacting drugs being prescribed together

Combinations that are unlikely to be prescribed are of little clinical relevance.

of individual drugs. For example, the similarity in mechanisms of action between carbamazepine and oxcarbazepine may explain why neurotoxic effects are more common when oxcarbazepine is used with carbamazepine than when used with other AEDs.49

Susceptibility to drug interactions

The probability of a drug interaction occurring and the associated clinical consequences are dependent on several factors (panel). Apart from the characteristics of the drugs, patient-related factors have an important role. For example,

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the effect of a metabolic interaction on a specific CYP isoenzyme can vary among patients in relation to genetic and environmental factors that determine the contribution of that isoenzyme to overall drug elimination. Age is another important source of variability. Most AED interactions described in this article have been reported in adults, but they are expected to happen in children as well. The magnitude and clinical significance of such interactions, however, may differ between children and adults owing to age-related pharmacokinetic and pharmacodynamic variations. In particular, the contribution of different CYP and UGT isoenzymes to drug metabolism (and the consequent implications of inducing or inhibiting these isoenzymes) undergoes important changes during development.50 CYP- dependent metabolism is low at birth (about 50–70% of adult levels), but by 2–3 years of age activity exceeds adult levels.51,52 Although glucuronidation is deficient at birth, owing to low concentrations of UGTs, adult levels of activity are reached by 3–4 years.53 Furthermore, children may exhibit higher levels of induction than adults.54,55 Changes in metabolic profile are also seen in elderly people. For example, the decline in metabolic capacity commonly observed in old age is greater for pathways catalysed by CYP enzymes than for reactions involving glucuronide conjugation.56,57 Elderly people have been reported to show a reduced responsiveness to enzyme induction.58,59 However, a recent study showed no evidence of this reduction in elderly patients treated with carbamazepine or phenobarbital.60 Finally, elderly people tend to be more sensitive to the adverse effects of centrally active drugs, and a given change in plasma concentrations of AEDs caused by a drug interaction may have a greater clinical effect in them than in young people.61

Interactions between AEDs

Interactions mediated by enzyme induction

Carbamazepine, phenytoin, phenobarbital, and primidone are potent inducers of various CYP isoenzymes (table 1) and they also induce UGT and epoxide hydrolases.2,25,38,62,63 As a result, these compounds stimulate the metabolism of other AEDs, most notably valproic acid,64,65 tiagabine,66 ethosuximide,67 lamotrigine,68–70 topiramate,71 zonisamide,72 oxcarbazepine and its active monohydroxy-metabolite,73 felbamate,74 and many benzodiazepine drugs.75,76 (table 2). The metabolism of carbamazepine can be stimulated by phenytoin or barbiturates.60,77–79

The feature common to all these interactions is a pronounced decrease in the steady-state plasma concentration of the affected drug. For example, the plasma concentration of valproic acid can be reduced on average by 76%, 49%, and 66% in patients who are also treated with phenobarbital, phenytoin, and carbamazepine, respectively.63 In some cases, these interactions have small clinical consequences because the loss of efficacy caused by the decreased concentration of the affected drug is compensated for by the independent anticonvulsant effect of the enzyme-inducing agent. In other cases, however, the decrease in plasma concentration of the affected drug has adverse effects on seizure control (figure 1), and an increase in dose is then indicated (figure 2). The plasma

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Interactions between antiepileptic drugs

Review

Table 2. Expected changes in plasma concentrations when an AED is added to a pre-existing regimen

AED added

PB PHT

PB PHT PRM

·· PHT↑↓ NCCP PB↑ ·· PRM↓

ETS CBZ VPA

ETS⇓ CBZ⇓ VPA⇓ ETS⇓ CBZ⇓ VPA⇓

ETS⇓ CBZ⇓ VPA⇓ ·· ↔ VPA↓ ETS⇓ ·· VPA⇓

ETS↑↓ CBZ-E↑ ··

? CBZ↓ ↔ NE ↔↔ NE ↔↔ NE ↔ VPA↓ NE ↔↔ NE ↔↔ NE CBZ↑↓ ↔ NE CBZ↑ ↔

OXC LTG GBP

H-OXC↓ LTG⇓ ↔ H-OXC↓ LTG⇓ ↔

? LTG⇓ ↔ NE NE NE H-OXC↓ LTG⇓ ↔

TPM TGB LEV

TPM⇓ TGB⇓ ↔ TPM⇓ TGB⇓ ↔

TPM⇓ TGB⇓ ↔ NE NE NE TPM⇓ TGB⇓ ↔

ZNS VGB FBM

ZNS⇓ ↔ FBM⇓ ZNS⇓ ↔ FBM⇓

ZNS⇓ ↔ FBM⇓ NE NE NE ZNS⇓ NE FBM⇓

↔ NE ↔ ? NE ? ↔ NE NE NE NE NE ? NE ? NE NE NE NE NE NE ·· NE ? NE ·· NE

? ↔ ··

PB↑ PRM NCCP PHT↑↓ ··

ETS ↔ CBZ ↔

VPA PB⇑ OXC PB↑ LTG ↔ GBP ↔ TPM ↔ TGB ↔ LEV ↔ ZNS ↔ VGB PB↓

FBM PB⇑

↔ NE PHT↑↓ PRM↓

PB↑ PHT↓* PB⇑

PHT↑ ?

↔ NE

↔ NE PHT↑ ↔ ↔↔ ↔↔ ↔NE PHT↓ PRM↓

↔ LTG⇑ ↔ TPM↓ ↔ ·· LTG↓ NE ? ? NE ·· NE NE NE NE NE ·· NE NE ? ? NE ·· ? NE NE NE NE ·· NE ↔ ↔ NE NE ? ↔ NE NE NE NE NE NE NE NE

↔ ↔ NE ??

↔

NE

↔ ↔ NE NE ·· NE NE

NE

PB↓

PHT⇑?? CBZ↓ VPA⇑

CBZ-E↑

Pre-existing AED

PB=phenobarbital; PHT=phenytoin; PRM=primidone; ETS=ethosuximide; CBZ=carbamazepine; VPA=valproic acid; OXC=oxcarbazepine; LTG=lamotrigine; GBP=gabapentin; TPM=topiramate; TGB=tiagabine; LEV=levetiracetum; ZNS=zonisamide; VGB=vigabatrin; FBM=felbamate; H-OXC=10-hydroxy-oxcarbazepine (active metabolite of OXC); CBZ- E=carbamazepine-10,11-epoxide. NE=none expected; *free (pharmacologically active) concentration may increase; NCCP=not commonly coprescribed; ↔=No change; ↓=a minor (or inconsistent) decrease in plasma concentration; ⇓=a clinically significant decrease in plasma concentration; ↑=a minor (or inconsistent) increase in plasma concentration; ⇑=a clinically significant increase in plasma concentration

concentration of carbamazepine, valproic acid, tiagabine, and lamotrigine are most significantly affected by enzyme induction, and doses of these drugs may need to be increased.62 Clinically important stimulation of lamotrigine metabolism has also been described in patients also treated with methsuximide.80,81

When enzyme induction leads to formation of active metabolites, the consequence of the interaction may be, paradoxically, a potentiation of the affected drug. One possible example of this effect is the stimulation of primidone metabolism in patients also treated with phenytoin, phenobarbital, or carbamazepine.82 Because primidone is converted partly to phenobarbital, this interaction may result in enhanced production of the latter metabolite and increased pharmacological effects. Although stimulation of valproic-acid metabolism by enzyme inducing AEDs typically results in decreased plasma concentrations and effectiveness of valproic acid, this interaction may also lead to increased formation of hepatotoxic metabolites, which may explain why patients taking phenytoin, phenobarbital, and carbamazepine are more susceptible to valproate-induced liver toxicity.83

Because enzyme induction is reversible, effects can appear when the inducing agent is discontinued or substituted with another AED. Under these circumstances, the rate of metabolism of the affected agent will gradually decrease, and its plasma concentration may become toxic. After regimen change, careful monitoring of drug concentrations in the plasma and of clinical response is recommended to determine any need for dose adjustments as early as possible.30,31,84,85

Among second generation AEDs, gabapentin,86 vigabatrin,87,88 levetiracetam,89 lamotrigine,90 topiramate,91 tiagabine,92,93 and zonisamide 94 have no enzyme inducing

effects on the metabolism of other AEDs. In one study, topiramate reduced plasma lamotrigine concentrations by 40–50% in four of seven patients.95 However, a larger study did not replicate this finding.96 Oxcarbazepine stimulates the metabolism of lamotrigine (although less than carbamazepine),80 felbamate decreases plasma carbamazepine concentration (while increasing the concentration of the active metabolite carbamazepine- 10,11-epoxide),97 whereas vigabatrin may decrease the plasma concentration of phenytoin through an unidentified mechanism.98–100 These interactions are probably of limited clinical significance, although an increase in lamotrigine dose requirements may occur in patients who are also being given oxcarbazepine.80

Interactions mediated by enzyme inhibition

Valproic acid as an enzyme inhibitor

Among commonly used AEDs, valproic acid is the most notable inhibitor of drug metabolism; its most common effect is to increase the plasma concentrations of both phenobarbital101 and lamotrigine.102,103 On average, the increase in plasma phenobarbital concentration after dosing with valproic acid is 30–50%, but interindividual variability is large and a reduction in phenobarbital (or primidone) dose by up to 80% may be required to avoid side-effects— particularly sedation and cognitive impairment.101 Although the increase in plasma phenobarbital concentrations is mainly related to inhibition of CYP isoenzymes (probably CYP2C9 or CYP2C19), the effect of valproic acid on lamotrigine metabolism involves inhibition of the UGT1A4 enzyme, which glucuronates lamotrigine.39 The inhibition of lamotrigine metabolism is already maximum at valproic-acid doses within the typical target range (􏰀500 mg/day in an adult)104 and involves a substantial

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Interactions between antiepileptic drugs

AED monotherapy

Addition of second AED

Improved seizure control

Adverse effects

Seizure worsening

No change in seizure control

Synergistic effects can improve seizure control or increase adverse effects

Antagonistic effects can result in seizure worsening or no change in seizure control

If appropriate, adjust doses on the basis of clinical response

Concentrations have increased or decreased

Possible pharmacokinetic drug interaction

Or

Unsatisfactory control in about 30% of patients

Measure plasma concentrations of drug* Concentrations as expected

Possible pharmacodynamic drug interaction

Or

Inhibition of the drug metabolising enzymes can cause high concentrations of either the added or the baseline drug and result in either improved seizure control or increased adverse effects

Induction of the drug metabolising enzymes can cause low concentrations of either the baseline drug to cause worsening of seizure control or of the added drug to cause no change in seizure control

If appropriate, adjust the dose on the basis of plasma concentrations of drug

Figure 1. Effect of AED interactions on therapeutic outcome. *Plasma concentrations of drugs should be measured at the time of the clinical event (eg, patient complaining of side-effects) and drug dose adjusted accordingly. If the clinical status of the patient is unaffected, plasma drug concentrations should be measured under steady-state conditions, ideally just before ingestion of the next dose (trough). Reprinted with permission from Epilepsia, International League Against Epilepsy.2

lengthening of lamotrigine half-life, from 30 h to about 60 h.103 As a result of this, lamotrigine dose requirements are notably reduced in patients given valproic acid.62 The use of lamotrigine in a patient already being given valproic acid should be done with caution: the dose should be started low (25 mg on alternate days, in adults) and increased slowly to avoid problems related with a fast increment in plasma lamotrigine concentration, particularly skin rashes. However, there is no risk of rash if valproic acid is introduced in a patient already stabilised on lamotrigine, although in such a patient a reduction in the dose of lamotrigine (as a rule of thumb, by about 50%) is advisable as soon as the dose of valproate reaches about 250–500 mg/day in adults. As discussed previously, lamotrigine metabolism is increased by enzyme-inducing AEDs, and when a patient receives such an AED together with valproic acid, enzyme induction and enzyme inhibition tend to cancel each other out, and the rate of lamotrigine metabolism will approach that seen in patients on lamotrigine monotherapy.25

Valproic acid can inhibit the metabolism of other AEDs. In some patients, valproic acid inhibits phenytoin metabolism35 and causes an increase in the plasma

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concentration of free phenytoin.32 Owing to concurrent displacement of phenytoin from plasma protein binding sites, this interaction may not be apparent when monitoring is based solely on total phenytoin concentrations.36 Valproic acid can also inhibit the metabolism and increase the plasma concentration of free diazepam105 and lorazepam.106 Given the high therapeutic index of benzodiazepine drugs, the latter interactions are probably of limited clinical significance.

In patients taking carbamazepine, valproic acid can increase the concentration of the active metabolite carbamazepine-10,11-epoxide through inhibition of epoxide hydrolase, without any substantial changes in the concentration of the parent drug.107–109 Valpromide, an amide derivative of valproic acid that is thought to be a valproic-acid prodrug, also inhibits epoxide hydrolase but the effect is much greater than that seen with valproic acid. Thus, addition of valpromide to the therapeutic regimen of a patient stabilised on carbamazepine results in increases of up to eight times in carbamazepine-10,11- epoxide concentrations and signs of toxicity in many cases.110 For patients treated with carbamazepine, valpromide and valproic acid should not be used interchangeably.

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Consider introduction of second AED

Introduce second AED

AED monotherapy

Seizure control

Unsatisfactory seizure control

Second AED associated with pharmacokinetic interactions

Second AED not associated with pharmacokinetic interactions

Second AED is an enzyme inducer

Second AED is an enzyme inhibitor

Metabolism of second AED induced by first AED

Metabolism of second AED inhibited by first AED

Dose adjustments will depend on the type of interaction

Dose of first AED may need to be decreased to avoid adverse effects

A higher dose of the second AED may be necessary to achieve seizure control

Figure 2. Drug interaction considerations in AED polytherapy. Reprinted with permission from Epilepsia, International League Against Epilepsy.2

Enzyme inhibition caused by other AEDs

Inhibitory drug interactions caused by AEDs other than valproic acid are less common. Because phenobarbital and phenytoin are metabolised by the same enzyme system, they may each inhibit metabolism of the other but the interaction is complicated by the fact that both compounds may also act as enzyme inducers. In general, phenytoin tends to cause a small increase in plasma phenobarbital concentration,111,112 though this has not been observed in all studies.113 The reverse interaction is more complex and unpredictable.114,115 Decreases, increases, or no change in plasma concentration of phenytoin have been described in patients given adjunctive phenobarbital therapy.115

Oxcarbazepine is a weak inhibitor of the CYP2C19 isoenzyme, which is involved in phenytoin metabolism. As a result, oxcarbazepine—particularly when used at high doses (>1800 mg/day)—may increase plasma phenytoin concentrations by up to 40%.49,116 Carbamazepine can also cause a modest increase in plasma phenytoin concentration,116 but this interaction is inconsistent. Topiramate is also a weak inhibitor of CYP2C19, which might explain its ability to increase plasma concentrations of phenytoin in a few patients.117 Most of these interactions are of small clinical significance.

Of all the AEDs, felbamate is by far the most potent and broad ranging inhibitor of drug metabolism and may increase plasma concentration of phenytoin,118 valproic acid,119 phenobarbital,120 carbamazepine-10,11-epoxide,97 and N-desmethyl-clobazam.121 These interactions are clinically important, but they will not be discussed in detail because

felbamate, owing to its serious liver and bone marrow toxicity, is only rarely used in the treatment of epilepsy. Sultiame, another potent inhibitor of the metabolism of phenytoin122 and phenobarbital,114 is also rarely used.

Pharmacodynamic interactions

Potentially beneficial interactions

Although the suggestion has been made that the combination of AEDs with different mechanisms of action should be pharmacodynamically more advantageous than combinations of drugs with the same mechanism, our understanding of the modes of action of individual drugs is insufficient to allow a fully mechanistic approach to AED therapy.42,123 Nevertheless, clinical evidence does indicate that some combinations are more beneficial than others. One example is the pharmacodynamic interaction between valproic acid and ethosuximide, which may lead to control of absence seizures in patients refractory to either drug given alone.124 Although the combined use of lamotrigine and valproic acid is complicated by the inhibition of lamotrigine metabolism, several studies have provided evidence that the remarkable effectiveness of this combination against refractory complex partial seizures,125 absence seizures,126 and other seizure types127,128 can only be explained by a pharmacodynamic interaction. Patients receiving this combination, however, may also experience pronounced toxicity, particularly hand tremor, and the dose of both drugs should be adjusted in such cases.125,129 Other AED combinations for which favourable pharmacodynamic interactions have been claimed include carbamazepine

For personal use. Only reproduce with permission from The Lancet Publishing Group.

A lower dose of the second AED may be necessary for seizure control and to avoid adverse effects

AED dosage need not take into consideration complications resulting from pharmacokinetic interactions. Monitor patient carefully because pharmacodynamic interactions are still possible

Dose of first AED may need to be increased to optimise seizure control

353

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Review

Interactions between antiepileptic drugs

Search strategy and selection criteria

Data for this review were identified by searches of Medline and PubMed with the terms “antiepileptic drug interactions” combined with individual drug names and drug groups; references from relevant articles; and searches of the authors’ files. Searches were undertaken between the period Sept 2, 2002 and Feb 11, 2003. Abstracts were included only when a complete published article was not available. Only papers published in English were reviewed. The purpose of the article was not to provide an exhaustive review of all interactions, but to highlight those which, based on the authors’ judgment, have the greatest importance in terms of clinical consequences and probability of concurrent use.

with valproic acid,130–133 valproic acid with clonazepam,134 carbamazepine with vigabatrin,133 lamotrigine with vigabatrin,135 lamotrigine with topiramate,136 lamotrigine with gabapentin,137 and vigabatrin with tiagabine.138 With the exception of valproic acid with ethosuximide or lamotrigine, clinical evidence for these positive pharmacodynamic interactions is mostly anecdotal.

Potentially adverse interactions

Adverse pharmacodynamic AED interactions are equally common.139 When excessive polytherapy is used, neurotoxic effects of AEDs may add up without appreciable gain in seizure control, and in this situation the advantage of reducing drug load has been clearly documented.140,141 In some patients, pharmacodynamic interactions related to excessive drug load may lead to worsening of seizures,142 and seizure control on reduction of complex combination therapies is not uncommon. There is also evidence that specific combinations are less well tolerated than others. In particular, pharmacodynamic interactions leading to neurotoxicity have been reported in some patients taking combinations of carbamazepine with oxcarbazepine49 or with lamotrigine,127,143 possibly related to additive blockade of voltage-gated sodium channels. A pharmacodynamic mechanism may also explain the rare occurrence of an encephalopathy characterised by stupor or even coma in some patients given valproate in combination with other AEDs, particularly phenobarbital.144

Prevention and management of adverse AED interactions

AED interactions can have substantial effects on clinical outcome (figure 1), and a therapeutic algorithm for management options in response to such interactions has been proposed (figure 2). A few simple rules can help to limit adverse consequences of AED interactions.2,139 Multiple drug therapy should be used only when it is clearly indicated. Most patients with epilepsy can be best managed with an individualised dose of a single AED. Most interactions are metabolically based and can be predicted from knowledge of the isoenzymes involved in the metabolism of the most commonly used drugs and the effects of these drugs on the same isoenzymes. Physicians should be aware of the most important interactions, underlying mechanisms, and any corrective action required

(eg, changes to dose). Combination of AEDs with similar adverse effect profiles (eg, benzodiazepines and barbiturates) should be avoided and combinations for which there is clinical evidence of favourable interactions should be preferentially selected. The clinical response to new drugs introduced or discontinued from the patient’s regimen should be carefully monitored. Unexpected responses to a change in the regimen could result from interaction between AEDs and the dose should be adjusted when appropriate.

If a pharmacokinetic interaction is anticipated, the plasma concentration of the affected drug should be monitored. Physicians should be aware that under certain circumstances (eg, in the presence of drug displacement from plasma proteins), routine total drug concentration measurements can be misleading and patient management may benefit from monitoring of free drug concentrations. In some cases, dose adjustments may have to be implemented at the time the interacting drug is added or removed.

Acknowledgments

The work of PNP is supported by the UK National Society for Epilepsy, University College Hospitals NHS Trust and the Institute of Neurology, University College London. The work of EP is supported by a University of Pavia Research Grant (FAR 1999-2002).

Authors’ contribution

Both authors contributed equally to this work.

Conflict of interest

The authors have no conflicts of interest.

Role of the funding source

Funders of the work of PNP and EP had no role in the writing of this review or the decision to submit the review for publication.

References

1 Beghi E, Perucca E. The management of epilepsy in the 1990s: acquisitions, uncertainties and perspectives for future research. Drugs 1995; 49: 680–94.

2 Patsalos PN, Froscher W, Pisani F, van Rijn C. The importance of drug interactions in epilepsy therapy. Epilepsia 2002; 43: 365–85.

3 Patsalos PN. Phenobarbitone to gabapentin: a guide to 82 years of anti-epileptic drug pharmacokinetic interactions. Seizure 1994; 3: 163–70.

4 Patsalos PN, Duncan JS. Antiepileptic drugs: A review of clinically significant drug interactions. Drug Safety 1993; 9: 156–84.

5 Patsalos PN. Pharmacokinetic and pharmacodynamic interactions: Principles and interpretative pitfalls. Epileptologia 1998; 6 (suppl 2): 9–19.

6 Bauer LA. Interference of oral phenytoin absorption by continuous nasogastric feeding. Neurology 1982; 32: 570–72.

354

7 Hatton RC. Dietery interaction with phenytoin. Clin Pharm 1984; 3: 110–11.

8 Worden Jr JP, Wood Jr CA, Workman CH. Phenytoin and nasogastric feedings. Neurology 1984; 34: 132.

9 Lin JH, Yamazaki M. Role of P-glycoprotein in pharmacokinetics. Clin Pharmacokinet 2003; 42: 59–98.

10 Hoffmeyer S, Burk O, von Richter O, et al. Functional polymorphisms of the human multidrug resistance gene: multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo. Proc Natl Acad Sci USA 2000; 97: 3473–78.

11 Fricker G, Drewe J, Huwyler J. Gutmann H, Begninger C. Relevance of P-glycoprotein for the enteral absorption of cyclosporine A: in vitro-in vivo correlation. Br J Pharmacol 1996; 118: 1841–47.

12 Lown KS, Mayo RR, Leichtman AB, et al. Role of intestinal P-glycoprotein (mdr1) in interpatient variation in the oral bioavailability of cyclosporin. Clin Pharmacol Ther 1997; 62: 248–60.

13 Meerum Terwgot JM, Malingre MM, Beijnen JH,

et al. Co-administration of oral cyclosporin A enables oral therapy with paclitaxel. Clin Cancer Res 1999; 5: 3379–84.

14 Malingre MM, Richel DJ, Beijnen JH, et al. Coadministration of cyclosporine strongly enhances the oral bioavailability of decetaxel. J Clin Oncol 2001; 19: 1160–66.

15 Potschka H, Fedrowitz M, Loscher W. P-glycoprotein and multidrug resistance-associated protein are involved in the regulation of extracellular levels of the major antiepileptic drug carbamazepine in the brain. Neuroreport 2001; 12: 3557–60.

16 Rizzi M, Caccia S, Guiso G, et al. Limbic seizures induce P-glycoprotein in rodent brain: functional implications for pharmacoresistance. J Neurosci 2002; 22: 5833–39.

17 Potschka H, Loscher W. Multidrug resistance- associated protein is involved in the regulation of extracellular levels of phenytoin in the brain. Neuroreport 2001; 12: 2387–89.

For personal use. Only reproduce

with permission from The Lancet Publishing Group.

THE LANCET Neurology Vol 2 June 2003 http://neurology.thelancet.com

Interactions between antiepileptic drugs

Review

18 Potschka H, Fedrowitz M, Loscher W. P- Glycoprotein-mediated efflux of phenobarbital, lamotrigine, and felbamate at the blood-brain barrier: evidence from microdialysis experiments in rats. Neurosci Lett 2002; 327: 173–76.

19 Sisodiya SM. Mechanisms of antiepileptic drug resistance. Curr Opin Neurol 2003; 16: 197–201.

20 Cox DS, Scott KR, Gao H, Eddington ND. Effect of P-glycoprotein on the pharmacokinetics

and tissue distribution of enaminone anticonvulsants: analysis by population and physiological approaches.

J Pharmacol Exp Ther 2002; 302: 1096–104.

21 Wacher VJ, Wu CY, Benet LZ. Overlapping substrate

specificities and tissue distribution of cytochrome P4503A and P-glycoprotein: implications for drug delivery and activity in cancer chemotherapy.

Mol Carcinog 1995; 13: 129–34.

22 Schuetz EG, Beck WT, Schuetz JD. Modulators and substrates of P-glycoprotein and cytochrome P4503A coordinately up-regulated these proteins in human carcinoma cells. Mol Pharmacol 1996; 49: 311–18.

23 Jette L, Beaulieu E, Leclerc JM, Beliveau R. Cyclosporin A treatment induces overexpression of P-glycoprotein in the kidney and other tissues.

Am J Physiol 1996; 270: F756–65.

24 Verschraagen M, Koks CHW, Schellens JHM, Beijnen JH. P-glycoprotein system as a determinant of drug interactions: the case of digoxin-verapamil. Pharmacol Res 1999; 40: 301–06.

25 Perucca E. The clinical pharmacology and therapeutic use of the new antiepileptic drugs. Fund Clin Pharmacol 2001; 15: 405–17.

26 Von Moltke LL, Greenblatt DJ, Schmider J, Wright CE, Harmatz J, Schader RI. In vitro approaches to predicting drug interactions in vivo. Biochem Pharmacol 1998; 55: 113–22.

27 Rolan PE. Plasma protein binding displacement interactions: Why are they still regarded as clinically important? Br J Clin Pharmacol 1994; 37: 125–28.

28 Sansom LN, Evans AM. What is the true clinical significance of plasma protein binding displacement interactions? Drug Safety 1995; 12: 227–33.

29 Benet LZ, Hoener BA. Changes in plasma protein binding have little clinical relevance. Clin Pharmacol Ther 2002; 71: 115–21.

30 Patsalos PN. Therapeutic drug monitoring in epilepsy: principles and concepts. Epilepsy Monit 2001; 5: 1-6.

31 Patsalos PN. Therapeutic drug monitoring in epilepsy : the established and the new antiepileptic drugs. Epilepsy Monit 2002; 6: 1–8.

32 Perucca E, Hebdige S, Frigo GM, Gatti G,

Lecchini S, Crema A. Interaction between phenytoin and valproic acid: Plasma protein binding and metabolic effects. Clin Pharmacol Ther 1980; 28: 779–89.

33 Patsalos PN, Lascelles PT. Effect of sodium valproate on plasma protein binding of diphenylhydantoin.

J Neurol Neurosurg Psychiat 1977; 40: 570–74.

34 Tsanaclis LM, Allen J, Perucca E, Routledge PA, Richens A. Effect of valproate on free plasma phenytoin concentrations. Br J Clin Pharmacol 1984; 18: 17–20.

35 Patsalos PN, Lascelles PT. In vitro hydroxylation of diphenylhydantoin and its inhibition by other commonly used anticonvulsants. Biochem Pharmacol 1977; 26: 1929–33.

36 Riva R, Albani F, Contin M, et al. Time-dependent interaction between phenytoin and valproic acid. Neurology 1985; 35: 510–15.

37 Patsalos PN, Elyas AA, Ratnaraj N, Iley J. Concentration-dependent displacement of tiagabine by valproic acid. Epilepsia 2002; 43 (suppl 8): 143.

38 Anderson GD. A mechanistic approach to antiepileptic drug interactions. Ann Pharmacother 1998; 32: 554–63.

39 Spina E, Perucca E, Levy RH. Predictability of metabolic antiepileptic drug interactions. In: Majkowski J, Bourgeois B, Patsalos PN, Mattson RH, eds. Antiepileptic drug: combination therapy and interactions. Cambridge: Cambridge University Press, (in press).

40 Perucca E, Hedges A, Makki KA, Ruprah M,

Wilson JF, Richens A. A comparative study of the enzyme inducing properties of anticonvulsant drugs in epileptic patients. Br J Clin Pharmacol 1984; 18: 401–10.

41 Su T, He W, Gu J, Lipinskas TW, Ding X. Differential xenobiotic induction of CYP2A5 in mouse liver, kidney, lung, and olfactory mucosa. Drug Metab Dispos 1998; 26: 822–24.

42 Perucca E. Clinical implications of hepatic microsomal enzyme induction by antiepileptic drugs. Pharmacol Ther 1987; 33: 139–44.

43 Patsalos PN, Duncan JS, Shorvon SD. Effect of the removal of antiepileptic drugs on antipyrine kinetics in patients taking polytherapy. Br J Clin Pharmacol 1988; 26: 253–59.

44 Rendic S, Di Carlo FJ. Human cytochrome P450 enzymes: a status report summarizing their reactions, substrates, inducers, and inhibitors. Drug Metab Rev 1997; 29: 413–580.

45 Green MD, Bishop WP, Tephley TR. Expressed human UGT1.4 protein catalyzes the formation of quaternary ammonium-linked glucuronides. Drug Metab Disp 1995; 23: 299–302.

46 Bonate PL, Reith K, Weir S. Drug interactions at the renal level. Implications for drug development.

Clin Pharmacokinet 1998; 34: 375–404.

47 Powell JR, Nelson E, Conrad KA, Likes K, Byers J III, Perrier D. Phenobarbital clearance, elimination with alkaline diuresis, and bioavailability in adults.

Clin Pharmacol Ther 1981; 29: 273.

48 Perucca E, Levy RH. Combination therapy and drug interactions. In: Levy RH, Mattson RH, Meldrum BS, Perucca E, eds. Antiepileptic Drugs, 5th edn. Philadelphia: Lippincott Williams and Wilkins, 2002: 96–102.

49 Barcs G, Walker EB, Elger CE, et al. Oxcarbazepine placebo-controlled, dose-ranging trial in refractory partial epilepsy. Epilepsia 2000; 41: 1597–607.

50 Anderson GD. Children versus adults: Pharmacokinetic and adverse-effect differences. Epilepsia 2002; 43 (suppl 3): 53–59.

51 Stewart CF, Hampton EM. Effect of maturation on drug disposition in pediatric patients. Clin Pharm 1987; 6: 548–64.

52 Morselli PL, Franco-Morselli R, Bossi L. Clinical pharmacokinetics in newborns and infants: age- related differences and therapeutic implications. Clin Pharmacokinet 1980; 5: 485–527.

53 Dalton GJ. Developmental aspects of drug conjugation with special reference to glucuronidation. Ann Rev Pharmacol Toxicol 1978; 18: 17–35.

54 Suzuki Y, Cox S, Hayes J, Walson PD. Valproic acid dosage necessary to maintain therapeutic concentrations in children. Ther Drug Monit 1991; 13: 314–17.

55 Cloyd JC, Kriel RL, Fischer JH, Sawchuk RJ, Eggerth RM. Pharmacokinetics of valproic acid in children: I. multiple antiepileptic drug therapy. Neurology 1983; 33: 185–91.

56 Schmucker DL. Liver function and phase I drug metabolism in the elderly: a paradox. Drugs Aging 2001; 18: 837–51.

57 Tanaka E. In vivo age-related changes in hepatic drug-oxidizing capacity in humans. J Clin Pharm Ther 1998; 23: 247–55.

58 Salem SA, Rajjayabun P, Shepherd AM,

Stevenson IH. Reduced induction of drug metabolism in the elderly. Age Ageing 1978; 7: 68–73.

59 Twum-Barima Y, Finnigan T, Habash AI, Cape RD, Carruthers SG. Impaired enzyme induction by rifampicin in the elderly. Br J Clin Pharmacol 1984; 17: 595–97.

60 Battino D, Croci D, Mamoli D, Messina S, Rossini A, Perucca E. Serum carbamazepine concentrations in elderly patients: a case-matched pharmacokinetic evaluation based on therapeutic drug monitoring data. Epilepsia (in press).

61 Parker BM, Cusack BJ, Vestal RE. Pharmacokinetic optimisation of drug therapy in elderly patients. Drugs Aging 1995; 7: 10–18.

62 Perucca E, Dulac O, Shorvon S, Tomson T. Harnessing the clinical potential of antiepileptic drug therapy: dosage optimisation. CNS Drugs 2001; 15: 609–21.

63 May T, Rambeck B. Serum concentrations of valproic acid: influence of dose and comedication. Ther Drug Monit 1985; 7: 387–90.

64 Perucca E, Gatti G, Frigo GM, Crema A, Calzetti S, Visintini D. Disposition of sodium valproate in epileptic patients. Br J Clin Pharmacol 1978; 5: 495–99.

65 Cloyd JC, Dutta S, Cao G, et al. The Depacon Study Group. Valproate unbound fraction and distribution volume following rapid infusions in patients with epilepsy. Epilepsy Res 2003; 53: 19–27.

66 Samara EE, Gustavson LE, El-Shourbagy T, Locke C, Granneman GR, Sommerville KW. Population analysis of the pharmacokinetics of tiagabine in patients with epilepsy. Epilepsia 1998; 39: 868–73.

67 Giaccone M, Bartoli A, Gatti G, et al. Effects of enzyme inducing anticonvulsants on ethosuximide pharmacokinetics in epileptic patients. Br J Clin Pharmacol 1996; 41: 575–79.

68 May TW, Rambeck B, Jurgens U. Serum concentrations of lamotrigine in epileptic patients: the influence of dose and comedication. Ther Drug Monit 1996; 18: 523–31.

69 Bartoli A, Guerrini R, Belmonte A, Alessandri MG, Gatti G, Perucca E. The influence of dosage, age, and comedication on steady state plasma lamotrigine concentrations in epileptic children: a prospective study with preliminary assessment of correlation with clinical response. Ther Drug Monit 1997; 19: 252–60.

70 Armijo JA, Bravo J, Cuadrado A, Herranz JL. Lamotrigine serum concentration-to-dose ratio: influence of age and concomitant antiepileptic drugs and dosage implications. Ther Drug Monit 1999; 21: 182–90.

71 Gidal BE. Topiramate. Drug interactions. In: Levy RH, Mattson RH, Meldrum BS, Perucca E, eds, Antiepileptic Drugs, 5th edn. Philadelphia,: Lippincott Williams and Wilkins, 2002: 734–39.

72 Ojemann LM, Shastri RA, Wilenski AJ, et al.. Comparative pharmacokinetics of zonisamide (CI-912) in epileptic patients on carbamazepine or phenytoin monotherapy. Ther Drug Monit 1986; 8: 293–96.

73 Tartara A, Galimberti CA, Manni R, et al. The pharmacokinetic profile of oxcarbazepine and its active metabolite 10-hydroxycarbazepine in healthy subjects and in epileptic patients treated with phenobarbitone or valproic acid. Br J Clin Pharmacol 1993; 36: 366–68.

74 Wagner M, Graves NM, Marineau K, Holmes GB, Remmel RP, Leppik IE. Discontinuation of phenytoin and carbamazepine in patients receiving felbamate. Epilepsia 1991; 32: 398–406.

75 Khoo KC, Mendels J, Rothbert M, et al. Influence of phenytoin and phenobarbital on the disposition of a single oral dose of clonazepam. Clin Pharmacol Ther 1980; 28: 368–75.

76 Sennoune S, Mesdjian E, Bonneton J, Genton P, Dravet C, Roger J. Interactions between clobazam and standard antiepileptic drugs in patients with epilepsy. Ther Drug Monit 1992; 14: 269–74.

77 Johannessen SI, Strandjord RE. Concentration of carbamazepine (Tegretol) in serum and cerebrospinal fluid in patients with epilepsy. Epilepsia 1973; 14: 373–79.

78 Christiansen J, Dam M. Influence of phenobarbital and diphenylhydantoin on plasma carbamazepine levels in patients with epilepsy. Acta Neurol Scand 1973; 49: 543–46.

79 Tomson T, Spina E, Wedlund JE. Minor additive inducing effects of phenobarbital on carbamazepine clearance in patients on combined carbamazepine- phenytoin therapy. Ther Drug Monit 1987; 9: 117–19.

80 May TW, Rambeck B, Jurgens U. Influence of oxcarbazepine and methsuximide on lamotrigine concentrations in epileptic patients with and without valproic acid comedication: results of a retrospective study. Ther Drug Monit 1999; 21: 175–81.

81 Besag FM, Berry DJ, Pool R. Methsuximide lowers lamotrigine blood levels: a pharmacokinetic antiepileptic drug interaction. Epilepsia 2000; 41: 624–27.

82 Cloyd JC, Miller KW, Leppik IE. Primidone kinetics: effects of concurrent drugs and duration of therapy. Clin Pharmacol Ther 1981; 29: 402–07.

83 Kondo T, Kaneko S, Otani K, et al. Associations between risk factors for valproate hepatotoxicity and altered valproate metabolism. Epilepsia 1992; 33: 172–77.

84 Perucca E. Is there a role for therapeutic drug monitoring of new anticonvulsants? Clin Pharmacokinet 2000; 38: 191–204.

85 Johannessen SI, Bettino D, Berry DJ, et al. Therapeutic drug monitoring of the new antiepileptic drugs. Ther Drug Monit (in press).

86 Radulovic LL, Wilder BJ, Leppik IE, et al. Lack of interaction of gabapentin with carbamazepine and valproate. Epilepsia 1994; 35: 155–61.

87 Richens A. Pharmacology and clinical pharmacology of vigabatrin. J Child Neurol 1991; 6: 2S7–10.

88 Patsalos PN, Duncan JS. The pharmacology and pharmacokinetics of vigabatrin. Rev Contemp Pharmacother 1995; 6: 447–56.

89 Patsalos PN. Pharmacokinetic profile of levetiracetam: toward ideal characteristics. Pharmacol Therapeut 2000; 85: 77–85.

90 Posner J, Webster H, Yuen AWC. Investigation of the ability of lamotrigine, a novel antiepileptic drug, to induce mixed function oxygenase enzymes.

Br J Clin Pharmacol 1991; 32: 658P.

91 Patsalos PN. The pharmacokinetic profile of topiramate. Rev Contemp Pharmacother 1999; 10: 155–62.

92 Gustavson LE, Mengel HB. Pharmacokinetics of tiagabine, a 􏰁-aminobutyric acid-uptake inhibitor, in healthy subjects after single and multiple doses. Epilepsia 1995; 36: 605–11.

THE LANCET Neurology Vol 2 June 2003 http://neurology.thelancet.com

For personal use. Only reproduce with permission from The Lancet Publishing Group.

355

356

Review

Interactions between antiepileptic drugs

93 Wang XL, Patsalos PN. The pharmacokinetic profile of tiagabine. Rev Contemp Pharmacother 2002; 12: 225–33.

94 Mather GC, Shah J. Zonisamide. Drug interactions. In: Levy RH, Mattson RH, Meldrum BS, Perucca E, eds. Antiepileptic drugs, 5th edn. Philadelphia: Lippincott Williams and Wilkins, 2002. 881–84.

95 Wnuk W, Volanski A, Foletti G. Topiramate decreases lamotrigine concentrations. Ther Drug Monit 1999; 21: 449.

96 Berry DJ, Besac FM, Pool F, Natarajan J, Doose D. Lack of an effect of topiramate on lamotrigine serum concentrations. Epilepsia 2002; 43: 818–23.

97 Albani F, Theodore WH, Washington P, et al. Effect of felbamate on plasma levels of carbamazepine and its metabolites. Epilepsia 1991; 32: 130–32.

98 Rimmer EM, Richens A. Interaction between vigabatrin and phenytoin. Br J Clin Pharmacol 1989; 27: 27S–33S.

99 Tonini M, Gatti G, Manzo L, Olibet G, Coccini T, Perucca E. Vigabatrin does not affect the intestinal absorption of phenytoin in rat duodeno-jejunal loops in situ. Pharmacol Res 1992; 26: 201–05.

100 Gatti G, Bartoli A, Marchiselli R et al. Vigabatrin- induced decrease in serum phenytoin concentration does not involve a change in phenytoin bioavailability. Br J Clin Pharmacol 1993; 36: 603–06.

101 Kapetanovic IM, Kupferberg HJ, Porter RJ, Theodore W, Schulman E, Penry JK. Mechanism of valproate–phenobarbital interaction in epileptic patients. Clin Pharmacol Ther 1981; 29: 480–86.

102 Yuen AWC, Land G, Weatherley B, Peck AW. Sodium valproate inhibits lamotrigine metabolism. Br J Clin Pharmacol 1992; 33: 511–13.

103 Binnie CD, Van Emde Boas W, Kasteleijn Nolste Trenite DG, et al. Acute effects of lamotrigine (BW430C) in persons with epilepsy. Epilepsia 1986; 27: 248–54.

104 Gidal BE, Anderson GD, Rutecki PR, Shaw R, Lanning A. Lack of an effect of valproate concentration on lamotrigine pharmacokinetics in developmentally disabled patients with epilepsy. Epilepsy Res 2000; 42: 23–31.

105 Dhillon S, Richens A. Valproic acid and diazepam interaction in vivo. Br J Clin Pharmacol 1982; 13: 553–60.

106 Samara EE, Granneman RG, Witt GF, Cavanaugh JH. Effect of valproate on the pharmacokinetics and pharmacodynamics of lorazepam. J Clin Pharmacology 1997; 37: 442–50.

107 Pisani F, Caputo M, Fazio A, et al. Interaction of carbamazepine-10,11-epoxide, an active metabolite of carbamazepine, with valproate: a pharmacokinetic study. Epilepsia 1990; 31: 339–42.

108 McKee PJ, Blackshaw J, Butler E, Gilham RA,

Brodie MJ. Variability and clinical relevance of the interaction between sodium valproate and carbamazepine in epileptic patients. Epilepsy Res 1992; 11: 193–98.

109 Rambeck B, May T, Juergens U. Serum concentrations of carbamazepine and its epoxide and diol metabolites in epileptic patients: the influence of dose and comedication. Ther Drug Monit 1987; 9: 298–303.

110 Pisani F, Fazio A, Oteri G, et al. Sodium valproate and valpromide: Differential interactions with carbamazepine in epileptic patients. Epilepsia 1986; 27: 548–52.

111 Lambie DG, Johnson R. The effects of phenytoin on phenobarbitone and primidone metabolism.

J Neurol Neurosurg Psychiat 1981; 44: 148–51.

112 Windorfer A, Sauer W. Drug interactions during anticonvulsant therapy in childhood: diphenylhydantoin, primidone, phenobarbitone, clonazepam, nitrazepam, carbamazepine

and dipropylacetate. Neuropediatrie 1977; 8: 29–41.

113 Diamond W, Buchanan R. A clinical study of the

effect of phenobarbital on diphenylhydantoin

plasma levels. J Clin Pharmacol 1970; 10: 306–11.

114 Perucca E, Richens A. Antiepileptic drug

interactions. In: Frey HH, Janz D, Antiepileptic drugs, handbook of experimental pharmacology, volume 74. Berlin: Springer-Verlag, 1985: 831–55.

115 Rambeck B. Antiepileptic drug interactions in polytherapy. Epileptologia 1998; 2: 43–53.

116 Lakehal F, Wurden CJ, Kalhorn TF, Levy RH.

Carbamazepine and oxcarbazepine decrease phenytoin metabolism through inhibition of CYP2C19. Epilepsy Res 2002; 52: 79–83.

117 Sachdeo RC, Sachdeo SK, Levy RH, et al. Topiramate and phenytoin pharmacokinetics during repetitive monotherapy and combination therapy to epileptic patients. Epilepsia 2002; 43: 691–96.

118 Graves NM, Holmes GB, Fuerst RH,

Leppik IE. Effect of felbamate on phenytoin and carbamazepine serum concentrations. Epilepsia 1989; 30: 225–29.

119 Wagner ML, Graves NM, Leppik IE, et al. The effect of felbamate on valproic acid disposition. Clin Pharmacol Ther 1994; 56: 494–502.

120 Reidenberg P, Glue P, Banfield CR, et al. Effects of felbamate on the pharmacokinetics of phenobarbital. Clin Pharmacol Ther 1995; 58: 279–87.

121 Contin M, Riva R, Albani F, Baruzzi A. Effect of felbamate on clobazam and its metabolite kinetics in patients with epilepsy. Ther Drug Monit 1999; 21: 604–08.

122 Houghton GW, Richens A. Inhibition of phenytoin metabolism by sulthiame in epileptic patients.

Br J Clin Pharmacol 1974; 1: 59–66.

123 Deckers CLP, Czuczwar SJ, Hekster YA, et al. Selection of antiepileptic drug polytherapy based on mechanisms of action: The evidence reviewed. Epilepsia 2000; 41: 1364–74.

124 Rowan AJ, Meijer JWA, de Beer-Pawlikowski N, van der Geest P, Meinardi H. Valproate- ethosuximide combination therapy for

refractory absence seizures. Arch Neurol 1983; 40: 797–802.

125 Pisani F, Oteri G, Russo MF, Di Perri R, Perucca E, Richens A. The efficacy of valproate–lamotrigine comedication in refractory complex partial seizures: evidence for a pharmacodynamic interaction. Epilepsia 1999; 40: 1141–46.

126 Ferrie CD, Robinson RO, Knott C, Panayiotopoulos CP. Lamotrigine as an add-on drug in typical

absence seizures. Acta Neurol Scand 1995; 91:

200–12.

127 Brodie MJ, Yuen AWC, and the 105 Study Group.

Lamotrigine substitution study: evidence for synergism with sodium valproate? Epilepsy Res 1997; 26: 423–22.

128 Ferrie CD, Panayiotopoulos CP. Therapeutic interaction of lamotrigine and sodium valproate in intractable myoclonic epilepsy. Seizure 1994; 3: 157–59.

129 Reutens DC, Duncan JS, Patsalos PN. Disabling tremor after lamotrigine with sodium valproate. Lancet 1993; 342: 185–86.

130 Gupta AK, Jeavons PM. Complex partial seizures: EEG foci and response to carbamazepine and sodium valproate. J Neurol Neurosurg Psychiat 1985; 48: 1010–14.

131 Ketter TA, Pazzaglia PJ, Post RM. Synergy of carbamazepine and valproic acid in affective illness: a case report and review of the literature. J Clin Psychopharmacol 1992; 12: 276–81.

132 Harden CL, Zisfein J, Atos-Radzion CE, et al. Combination valproate-carbamazepine therapy in partial epilepsies resistant to carbamazepine monotherapy. J Epilepsy 1993; 6: 91–94.

133 Brodie MJ, Mumford JP, 012 Study Group. Double- blind substitution of vigabatrin and valproate in carbamazepine-resistant partial epilepsy. Epilepsy Res 1999; 34: 199–205.

134 Mireles R, Leppik IE. Valproate and clonazepam comedication in patients with intractable epilepsy. Epilepsia 1985; 26: 122–26.

135 Stolarek I, Blacklaw J, Forrest G, Brodie MJ. Vigabatrin and lamotrigine in refractory epilepsy. J Neurol Neurosurg Psychiat 1994; 57: 921–24.

136 Stephen LJ, Sills GJ, Brodie MJ. Lamotrigine and topiramate may be a useful combination. Lancet 1998; 351: 958–59.

137 Pisani F, Oteri G, Antonino F, Di Perri R. Complete seizure control following gabapentin- lamotrigine combination. Epilepsia 1999; 40 (suppl 2): 253–54.

138 Leach JP, Brodie. Synergism with GABAergic drugs in refractory epilepsy. Lancet 1994; 343: 1650.

139 Perucca E. Pharmacological principles as a basis for

polytherapy. Acta Neur Scand 1995; 162 (suppl 1):

31–34.

140 Shorvon SD, Reynolds EH. Reduction in

polypharmacy for epilepsy. BMJ 1979; 27: 1023–25. 141 Perucca E. Overtreatment in epilepsy: adverse

consequences and mechanisms. Epilepsy Res 2002;

52: 25–33.

142 Perucca E, Gram L, Avanzini G, Dulac O.

Antiepileptic drugs as a cause of worsening of

seizures. Epilepsia 1998; 39: 5–17.

143 Besag FMC, Berry DJ, Pool F, Newbery JE, Subel B.

Carbamazepine toxicity with lamotrigine: pharmacokinetic or pharmacodynamic interaction? Epilepsia 1998; 39: 183–87.

144 Sackellares JC, Lee SI, Dreifuss FE. Stupor following administration of valproic acid to patients receiving other antiepileptic drugs. Epilepsia 1979; 20: 697–703.

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