Drug–Drug Interactions

Chapter 110

René H. Levy

Blaise F.D. Bourgeois

Houda Hachad

Introduction

Within the context of the pharmacologic treatment of epilepsy, the topic of drug interactions has received much attention. Because antiepileptic drugs (AEDs) have narrow therapeutic ranges, treatment is generally individualized, and unpredicted alterations in drug levels might require dose adjustments. Most of the older AEDs are prone to interactions with other AEDs, as well as with other concurrent medications such as anticoagulants, antidiabetic agents, and antidepressants. As a result, the literature associated with AED interactions is extensive. This chapter focuses on recent advances and the integration of pharmacokinetic and pharmacodynamic interactions.

Pharmacodynamic Interactions

The concept of pharmacodynamic interactions between AEDs is quite different from the concept of pharmacokinetic interactions. Whereas pharmacokinetic interactions determine changes in levels of a drug, pharmacodynamic interactions determine changes in pharmacologic effects when another drug is added or discontinued. These pharmacodynamic interactions, therefore, can determine whether it is meaningful for two particular drugs to be prescribed together. In contrast, pharmacokinetic interactions require only dose adjustments; they are unrelated to the qualitative aspects of drug combinations. The amount of information available about pharmacokinetic interactions between AEDs is considerably larger than that available about pharmacodynamic interactions, in part because it is easier to measure drug levels than to quantify various drug actions. In addition, for pharmacodynamic interactions, several pharmacologic actions of drugs can be involved, whereas with pharmacokinetic interactions there is always only one end point, namely, the drug concentration. To analyze pharmacodynamic interactions, it is necessary to understand what the possible interactions can be. Pharmacokinetic interactions can cause a change in drug absorption, metabolism, or elimination or a displacement from serum proteins. Pharmacodynamic interactions are distinguished by whether they are purely additive, supraadditive, or infraadditive. When the interaction is additive, the combined effect of the two drugs administered together for a given pharmacologic effect is equal to the expected sum of the corresponding activity of each drug used alone. For instance, if concentration x of drug A produces a certain effect, and concentration y of drug B produces the same effect, one-half of concentration x of A in the presence of one-half of concentration y of B will produce the same effect. One-half of x and one-half of y represent an equivalent “bolus,” and this concept forms the basis of the so-called “isobolographic” analysis, an established method for the quantitative assessment of pharmacodynamic interactions.²¹ When the interaction is supraadditive, or potentiated, the combined effect of the two drugs is greater than the expected sum of the individual effects of the two drugs. In the foregoing example, less than one-half the concentration of each drug would be required to achieve the same effect. Finally, if the interaction is infraadditive, or antagonistic, the combined effect is less than the expected sum of the individual effects, and, for instance, more than one-half the concentration of each drug would be required to achieve the same effect.

How does this apply to pharmacodynamic interactions between AEDs? AEDs form a heterogeneous group; their common denominator is the ability to prevent the occurrence of seizures. They also all tend to produce toxicity, in particular neurologic toxicity, at certain concentrations. The antiepileptic pharmacodynamic interaction between two drugs is irrelevant in itself. A supraadditive interaction is not necessarily beneficial. The concentration of a single drug could be increased indefinitely if it were not for the occurrence of toxicity. The same upper limit, however, will also apply to two drugs administered simultaneously. Therefore, for a combination of two AEDs to be advantageous, the seizure protection provided by the combination at a certain degree of toxicity (e.g., the threshold for overt toxicity) must be stronger than that with either drug alone at the same level of toxicity. Thus, the antiepileptic and the neurotoxic interactions must differ in favor of the antiepileptic interaction. In clinical reality, this issue is complicated by the fact that side effects of AEDs are not limited to neurotoxicity. In addition, a totally different situation in which a combination of two AEDs can be advantageous can arise when a patient has two different seizure types, each of which responds to a different drug.

Based on these considerations, it is understandable that the information on pharmacodynamic interactions between AEDs is limited. These interactions are difficult to quantify in patients. Even the available data from animal experiments are limited because certain studies considered only the antiepileptic interaction. In many other studies, the analysis was based on doses only. When drug effects are quantified on the basis of drug dose alone, pharmacokinetic interactions can falsify the analysis of pharmacodynamic interactions. For instance, earlier studies based on the analysis of doses in animals suggested an antiepileptic potentiation between phenytoin and phenobarbital.²⁸^,¹⁷² This turned out to be a pharmacokinetic artifact due to an acute inhibition of phenytoin elimination in the presence of phenobarbital. Later studies revealed that, in the presence of phenobarbital, single doses of phenytoin produce higher phenytoin brain levels than when phenytoin is administered alone and that the antiepileptic interaction between phenobarbital and phenytoin is purely additive when brain levels are used for the analysis.²⁰^,⁹¹

The results of the first series of experimental studies in which antiepileptic as well as neurotoxic interactions between AEDs were quantified are summarized in Table 1. These studies reveal that the majority of antiepileptic interactions are strictly additive and that antiepileptic potentiation is the exception

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rather than the rule. In contrast, neurotoxic interactions are divided about equally between those that are infraadditive and those that are additive. These experimental data suggest that only a few combinations among the older AEDs are possibly superior to the corresponding monotherapies. These combinations include valproate with carbamazepine, valproate with ethosuximide, and valproate with phenytoin. Although an infraadditive neurotoxic interaction between phenytoin and phenobarbital was found, the therapeutic index of phenobarbital alone was very low, and the combination still had a lower therapeutic index than did phenytoin alone.²⁰

Table 1 Pharmacodynamic interactions between antiepileptic drugs in animal models

	Interaction
Drug	Antiepileptic	Neurotoxic	Ref.
A. Older drugs
PHT + PB	Additive	Infraadditive	20
PHT + CBZ	Additive	Additive	129
CBZ + PB	Additive	Additive	27
VPA + PB	Additive	Additive	21
VPA + ESM	Additive	Infraadditive	22
VPA + CBZ	Additive	Infraadditive	21
VPA + PHT	Supraadditive	Additive	36
VPA + CZP	Supraadditive	Supraadditive	26
ESM + CZP	Supraadditive	Supraadditive	26
CBZ + CBZ-E	Additive	Additive	27
PRM + PB	Supraadditive	Infraadditive	25
PB + PEMA	Supraadditive	Supraadditive	25
B. Newer drugs
LTG + TPM	Supraadditive	Infraadditive	115
LTG + VPA	Supraadditive	Infraadditive	115
LTG + CBZ	Infraadditive	Additive	115
LTG + PB	Supraadditive	Supraadditive	115
LTG + PHT	Additive	Additive	115
TGB + GBP	Supraadditive	Additive	116
TPM + FBM	Supraadditive	Infraadditive	113
TPM + OXC	Supraadditive	Additive	113
OXC + FBM	Infraadditive	Additive	113
OXC + LTG	Infraadditive	Supraadditive	113
LTG + FBM	Additive	Infraadditive	114
OXC + GBP	Supraadditive	Additive	114
LEV + TPM	Supraadditive	Infraadditive	111
LEV + CBZ	Supraadditive	Infraadditive	112
LEV + OXC	Supraadditive	Infraadditive	112
CBZ, carbamazepine; CBZ-E, carbamazepine epoxide; CZP, clonazepam; ESM, ethosuximide; FBM, felbamate; GBP, gabapentin; LEV, levetiracetam; LTG, lamotrigine; OXC, oxcarbazepine; PB, phenobarbital; PEMA, phenyo-ethyl-malonamide (primidone metabolite); PHT, phenytoin; PRM, primidone; TGB, tiagabine; TPM, topiramate; VPA, Valproate. Source: Modified from Bourgeois BFD, Dodson WE. Antiepileptic and neurotoxic interactions between antiepileptic drugs, In: Pitlick WH, ed. Antiepileptic Drug Interactions. New York: Demos; 1988:209–219.

Interactions between low doses of clonazepam and valproate or ethosuximide were all found to be supraadditive for antiepileptic and for neurotoxic effects, but they result in a superior therapeutic index for both valproate and ethosuximide.²² Using a similar model, Gordon et al.⁶⁴ studied the pharmacodynamic interactions between felbamate and older AEDs. They found a potentiation of the antiepileptic activity of felbamate by phenytoin, carbamazepine, valproate, and phenobarbital. In contrast, the neurotoxicity was not potentiated, and the protective index of felbamate was raised by the addition of any one of these four drugs.

Many additional experimental studies of pharmacodynamic interactions have been carried out in recent years, involving mostly the newer AEDs (Table 1).³⁸ Overall, these studies again reveal that various combinations can have any possible type of association of antiepileptic and neurotoxic interactions. Accordingly, some drug combinations are more promising than others, at least on the basis of this experimental model.

In the end, whether a combination of two AEDs is beneficial for patients needs to be determined by careful clinical assessments. Although pharmacodynamic interactions are more difficult to study in patients than in experimental animals, valuable clinical data have accumulated. One of the first clinical studies addressing in a systematic manner the issue of the beneficial value of an AED combination was reported by Hakkarainen.⁷⁰ Among 100 newly diagnosed patients, 33 were refractory to carbamazepine alone and to phenytoin alone. Of those, five (15%) became seizure free on the combination. Rowan et al.¹⁴⁰ demonstrated that absence seizures could be fully controlled by valproate–ethosuximide combination therapy in a few

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patients who had been refractory to either drug alone. Walker and Koon¹⁶⁹ found that some patients who had not responded to valproate alone and to carbamazepine alone became seizure free on the combination.

A positive synergism between valproate and lamotrigine has also been suggested. Among 347 patients refractory to monotherapy with valproate, carbamazepine, phenytoin, or phenobarbital, the seizure reduction was significantly greater when lamotrigine was added to valproate than when it was added to the other drugs.²⁴ In a rigorous systematic study of add-on valproate versus add-on lamotrigine, among 13 patients who had not responded to the addition of either one of the two drugs, 4 became seizure free when both drugs were added.¹²³ When 14 patients whose seizures had not been controlled by monotherapy with carbamazepine and with vigabatrin were given both medications, 5 (36%) became seizure free.¹⁵⁹

In addition to potentially favorable pharmacodynamic interactions, clinical observations have also revealed that adverse effects of one AED can be potentiated by those of another. An increase in tremor when lamotrigine was prescribed in combination with valproate was observed in two studies.⁸⁰^,¹²³ An increase in side effects characteristic of carbamazepine was noted in four patients in whom levetiracetam was added to carbamazepine in polytherapy.¹⁵⁶ An exacerbation of carbamazepine toxicity also was noted after the addition of lamotrigine, and this could not be attributed to a pharmacokinetic interaction.¹⁶ Chorea occurred in three patients on phenytoin and lamotri-gine in combination only, and it resolved when one medication was tapered.¹⁷⁵ Finally, it appears that valproate encephalopathy is more likely to occur in the presence of another AED, and it can resolve when either valproate or the other drug is discontinued.¹⁰⁴ More recently, two reports suggested that the addition of topiramate may enhance some side effects of valproate, in particular hyperammonemic encephalopathy.⁶³^,¹⁰¹

Pharmacokinetic Interactions

Metabolic and Pharmacokinetic Characteristics of Antiepileptic Drugs

Table 2 summarizes the principal metabolic (enzymes with major or minor roles) and pharmacokinetic (route of elimination, half-life and extent of plasma protein binding) characteristics of older (established) and newer AEDs that are relevant to a mechanistic understanding of drug interactions.

Interactions Associated With Older Antiepileptic Drugs

Effects of Established Antiepileptic Drugs on Other Drugs

These interactions result principally from the induction of several metabolic enzymes (cytochrome P450 1A2 [CYP1A2], CYP2C9, CYP2C19, CYP3A4, and glucuronyl transferases) by carbamazepine, phenobarbital, phenytoin, or primidone and the inhibition of a few enzymes by valproic acid.

Table 3 provides a comprehensive listing of drugs affected by the enzyme-inducing effects of carbamazepine, phe-nytoin, and phenobarbital. These include many CYP3A4 substrates, narrow-therapeutic-range drugs such as warfarin, and drugs that are mainly glucuronidated such as lamotrigine. Recent studies show large decreases in serum concentrations for quetiapine (7.5-fold increase in clearance)⁶⁶ and tipifarnib (5-fold increase in clearance).³² CYP2B6 induction by phenyt- oin was observed in a patient taking two CYP2B6 substrates—thiothepa and cyclophosfamide.⁴¹

Valproic acid behaves as an inhibitor of CYP2C9, CYP2C19, and CYP3A4. It increases the serum levels of phenobarbital, phenytoin, and warfarin. It also inhibits some glucuronyl transferases and elevates the serum levels of lamotrigine⁵⁹ and other drugs such as lorazepam,¹⁴⁷ naproxen,¹ and zidovudine.⁹² The effects of valproic acid on lorazepam pharmacokinetics were studied in two groups with different uridine glucuronyl transferase (UGT) genotypes—UGT2B15*1/*1 and UGT2B15*2/*2. Results indicated that during the valproic acid–inhibited state, lorazepam clearance was lower in the *2/*2 group, although the percentage changes from baseline did not differ significantly by genotype.²⁹ Valproic acid produced small increases in area under the serum concentration curve (AUC) and in the peak serum concentration (C_max) of the recently approved drug aripiprazole with minimal effects on its active metabolite.³⁰). Because valproic acid has the potential to benefit patients suffering from HIV-associated cognitive impairment,¹⁴⁸ its effects were studied in HIV-1–infected patients receiving efavirenz or lopinavir/ritonavir. Valproic acid did not affect efavirenz disposition, but it increased lopinavir concentrations.⁴⁴

Effects of Other Drugs on Established Antiepileptic Drugs

Because established AEDs are substrates of metabolizing enzymes, they are subject to a number of interactions resulting from the inducing or inhibitory effects of coprescribed drugs. These interactions are summarized in Table 4. Inhibitors of CYP3A4, such as ketoconazole, clarithromycin, erythromycin, fluvoxamine, nefazodone, diltiazem, and ritonavir, increase carbamazepine levels. The CYP2C9/2C19-mediated metabolism of phenytoin is inhibited by fluconazole, sulfaphenazole, phenylbutazone, amiodarone, ticlopidine, and more recent drugs such as voriconazole. Other drugs known to reduce the clearance of (S)-warfarin (substrate of CYP2C9) such as zafirlukast are expected to affect phenytoin disposition in a similar fashion. Moreover, concomitant administration of lopinavir/ritonavir and phenytoin results in a two-way drug interaction: phenytoin increased lopinavir clearance via CYP3A4 induction, and lopinavir/ritonavir increased phenytoin clearance via CYP2C9 induction.⁹⁸

There are numerous case reports of decreased or increased valproate valproic acid exposure in the presence of known modulators of transport systems. In the case of carbapenem antibiotics, there is a consistent and marked decrease in valproic acid concentrations often accompanied by breakthrough seizures.³¹ The mechanisms of this decrease in valproic acid concentration have not been elucidated.¹¹⁵

Interactions Associated with Newer Antiepileptic Drugs

Recently developed AEDs as a group appear to exhibit fewer pharmacokinetic drug interactions. This is the result of a direct attempt to avoid or minimize oxidative metabolism when these drugs were developed (Table 2). Felbamate, lamotrigine, oxcarbazepine and its monohydroxy derivative (MHD), topiramate, and zonisamide are substrates for metabolizing enzymes (CYPs or UGTs), whereas gabapentin, levetiracetam, and vigabatrin are mostly eliminated by renal excretion.

Felbamate

Felbamate undergoes partial hepatic metabolism, with almost 50% of the dose excreted unchanged in the urine of healthy volunteers.

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Table 2 Pharmacokinetics and elimination pathways of antiepileptic drugs in adults

Drug	Half-life (h)	Protein binding (% bound)	Elimination (main route)	Enzyme with major role	Enzymes with minor role	Additional data
Older AEDs
Carbamazepine	5–26	75	Oxidation to 10,11-epoxide metabolite (65%); glucuronidation (15%)	CYP3A4	CYP1A2, CYP2C8	Epoxide metabolite is active and cleared by epoxide hydrolase
Ethosuximide	40–60		Oxidation (65%)	CYP3A4
Phenobarbital (primidone: prodrug)	77–128	55	Oxidation to p-hydroxy metabolite (20%); N-glucosidation; renal excretion	CYP2C9	CYP2C19 CYP2B6
Phenytoin	7–42	90	Oxidation to 5-(4-hydroxyphenyl)-5-phenylhydantoin (90%)	CYP2C9	CYP2C19
Valproic acid	9–15	90	Glucuronidation (50%); beta-oxidation (10%–20%)	UGT2B7	UGT1A6, 1A9	Beta-oxidation by mitochondrial oxidases and CYPs
Newer AEDs
Felbamate	16–22	20–25	Oxidation (15%); renal excretion	CYPs
Gabapentin	5–7	3	Renal excretion
Lamotrigine	30	55	Glucuronidation >65%	UGT1A4
Levetiracetam	6–8	10	Renal excretion; hydrolysis		Hydrolase	Hydrolysis (25%)
Oxcarbazepine (MHD active metabolite)	9 (MHD)	40 (MHD)	Glucuronidation (MHD)		Aldoketoreductase converts oxcarbazepine to MHD	Oxcarbazepine is a produg converted to MHD
Pregabalin	6		Renal excretion (>90%)
Tiagabine	7–9	98	Oxidation (>30%)	CYP3A4
Topiramate	18–23	15	Renal excretion; oxidation (15%)		CYP
S-Yigabatrin	4–7		Renal excretion
Zonisamide	63	40	Renal excretion; oxidation; reduction; N-acetylation	CYP3A4	N-Acetyltransferase
AED, antiepileptic drug; CYP, cytochrome P450; MHD, monohydroxy derivative; UGT, uridine glucuronyl transferase.

Table 3 Drugs whose serum concentrations are decreased by coadministration of carbamazepine, phenytoin, and phenobarbital

Coadministered agent	Drugs used in epilepsy whose concentration is decreased by the coadministered agent	Other drugs whose concentration is decreased by the coadministered agent
Carbamazepine	Alprazolam	Amitriptylline
	Clobazam	Albendazole
	Conazepam	Citalopram
	Clorazepate	Bromperidol
	Diazepam	Bupropion
	Midazolam	Caffeine
	Ethosuximide	Clozapine
	Felbamate	Cyclosporine
	Lamotrigine	Dexamethasone
	Levetiracetam	Doxepin
	Oxcarbazepine (MHD)	Doxycycline
	Phenobarbital	Etizolam
	Primidone	Felodipine
	Phenytoin	Fentanyl
	Tiagabine	Haloperidol
	Topiramate	Imipramine
	Valproate	Indinavir
	Zonisamide	Itraconazole
		Methylprednisolone
		Mianserin
		Mirtazapine
		Nefazodone
		Nifedipine
		Nimodipine
		Olanzapine
		Omeprazole
		Oral contraceptives
		Praziquantel
		Prednisolone
		Quetiapine
		Risperidone
		Simvastatin
		Trazodone
		Vecuronium
		Vincristine
		Warfarin
		Ziprazidone
Phenytoin	Carbamazepine	Acenocoumarol
	Clobazam	Acetaminophen
	Clonazepam	Albendazole
	Felbamate	Amiodarone
	Lamotrigine	Chloramphenicol
	Levetiracetam	Cyclophosphamide
	Methsuximide	Cyclosporine
	Phenobarbital	Dexamethasone
	Primidone	Dicoumarol
	Oxazepam	Digoxin
	Oxcarbazepine	Dispopyramide
	Tiagabine	Doxycycline
	Topiramate	Itraconazole
	Valproate	Irinotecan
	Zonisamide	Lopinavir
		Meperidine
		Methadone
		Methylprednisolone
		Mexiletine
		Mirtazapine
		Misonidazole
		Nisoldipine
		Oral contraceptives
		Oxazepam
		Praziquantel
		Prednisolone
		Prednisone
		Quetiapine
		Quinidine
		Ritonavir
		Sirolimus
		Theophylline
		Thiotepa
		Tirilazad
		Vecuromium
		Voriconazole
		Warfarin
Phenobarbital	Clobazam	Albendazole
(and primidone)	Clonazepam	Cimetidine
	Carbamazepine	Chloramphenicol
	Ethosuximide	Clozapine
	Lamotrigine	Cyclosporine
	Oxcarbazepine	Dexamethazone
	Phenytoin	Disopyramide
	Topiramate	Felodipine
	Valproic acid	Griseofulvine
	Zonisamide	Irinotecan
		Lidocaine
		Losartan
		Meperidine
		Methylprednisolone
		Metronidazole
		Misonidazole
		Nifedipine
		Nimodipine
		Oral Contraceptives
		Paroxetine
		Prednisolone
		Prednisone
		Quinidine
		Tacrolimus
		Teniposide
		Theophylline
		Tirilazad
		Verapamil
		Warfarin
MHD, monohydroxy derivative.

Table 4 Drugs that have been reported to inhibit the metabolism and to increase the serum concentration of carbamazepine, phenytoin, phenobarbital, and valproic acid

Affected drug	Metabolic inhibitor
Carbamazepine	Cimetidine
	Clarithromycin
	Danazol
	Dextropropoxyphene
	Diltiazem
	Erythromycin
	Fluconazole
	Fluoxetine
	Fluvoxamine
	Isoniazid
	Ketoconazole
	Metronidazole
	Nefazodone
	Quetiapine
	Risperidone
	Ritonavir
	Sertraline
	Ticlopidine
	Trazodone
	Troleandomycin
	Verapamil
	Viloxazine
Phenytoin	Allopurinol
	Amiodarone
	Azapropazone
	Capecitabine
	Chloramphenicol
	Cimetidine
	Chlorpheniramine
	Dextropopoxyphene
	Diltiazem
	Disulfiram
	Omeprazole
	Phenylbutazone
	Sulfinpyrazone
	Tamoxifen
	Ticlopidine
	Tolbutamide
	Doxifluridine
	Fluconazole
	Fluorouracil
	Fluoxetine
	Fluvoxamine
	Imipramine
	Isoniazid
	Miconazole
	Sertraline
	Sulfaphenazole
	Tamoxifen
	Tegafur
	Trazodone
	Viloxazine
	Voriconazole
Phenobarbital^a	Chloramphenicol
	Dextropropoxyphene
Valproic acid	Cimetidine
	Erythromycin
	Isoniazid
	Sertraline
	Stiripentol
^aIncluding phenobarbital derived metabolically from primidone.

Compounds with enzyme-inducing activity increase felbamate clearance: in two population pharmacokinetic studies, felbamate clearance was 40% higher when felbamate was coadministered with carbamazepine and phenytoin compared to monotherapy; however, phenobarbital treatment did not have any significant effect.¹¹^,⁸⁴ In a large retrospective evaluation, a prolongation in felbamate half-life from 24 to 32.4 hours was found in patients taking concomitantly gabapentin compared to monotherapy, but this effect is still unexplained.⁷⁵

The disposition of various AEDs can be altered by felbamate. Reductions in carbamazepine levels between 18% and 31% were observed when felbamate was coadministered, with corresponding increases in serum carbamazepine-10,11-epoxide (CBZ-E) levels of 33% to 57%.⁴^,⁶⁵^,¹⁶⁸ Recently, Egnell et al.⁵² suggested that induction of CYP3A4 is a possible mechanism for the interaction between felbamate and carbamazepine. Increases in estrogen and progestin clearance have also been associated with felbamate.¹⁴¹ The only isoform inhibited in vitro by therapeutic concentrations of felbamate was CYP2C19 (K_i = 225 μmol/L).⁶² This observation is consistent with clinical findings of increased serum concentrations of phenytoin⁶²^,⁶⁵^,¹⁴¹^,¹⁴³ and might account for the reduced clearance of phenobarbital¹³⁰ and the higher levels of norclobazam and clobazam³⁴ in patients comedicated with felbamate. Felbamate has also been shown to decrease valproic acid clearance by 20% to 50%, presumably via inhibition of the β-oxidation metabolic pathway.²¹^,²²^,²³^,²⁴^,²⁵^,³⁴^,⁶²^,¹³⁰^,¹⁴³^,¹⁶⁷

Lamotrigine

Effects of Other Drugs on the Disposition of Lamotrigine.

Lamotrigine is extensively metabolized by glucuronidation mediated by UGT1A4 and excreted in urine predominantly as the inactive 2N-glucuronide conjugate.¹⁵⁵ Comedication with enzyme-inducing AEDs enhances the metabolic clearance of lamotrigine through induction of UGT1A, and higher doses of lamotrigine are needed when the drug is given concurrently with phenytoin, carbamazepine, primidone, and phenobarbital.⁷^,¹⁰⁵^,¹⁰⁶ Oxcarbazepine and its corresponding monohydroxy metabolite are less potent enzyme inducers than carbamazepine, but they can also decrease serum lamotri-gine concentrations.¹⁰⁵ Methsuximide can also lower lamotri-gine levels, leading to deterioration in seizure control in some cases.¹⁵

When lamotrigine and felbamate were administered concurrently to 21 healthy individuals, serum concentrations of lamotrigine were similar to those obtained with lamotrigine and placebo,³³ and similar findings were obtained in patients.⁵⁷ Levetiracetam did not affect the steady-state serum concentrations of lamotrigine.⁵⁸^,¹²¹ Similarly, treatment with pregabalin, 600 mg/d for 7 days, had no effect on lamotrigine steady-state concentrations.²⁵ Coadministration of escalating doses of to-piramate in a group of 25 patients resulted in only slight decreases in average lamotrigine levels compared with baseline: lamotrigine levels were decreased 20% to 30% in three of the patients, consistent with the notion that topiramate is a weak enzyme inducer.¹⁴ Steady-state dosing of zonisamide in 20 patients stabilized on lamotrigine monotherapy (150 to 500 mg/d) did not significantly affect lamotrigine C_max, AUC, or clearance, but it decreased significantly renal lamotrigine clearance.⁹⁵ A 22% increase in lamotrigine clearance has been reported in healthy individuals after administration of retigabine; this interaction was unexpected because retigabine did not show enzyme induction in other interaction studies.⁷¹

Lamotrigine metabolism is strongly inhibited by valproic acid, resulting in twofold increases in lamotrigine half-life and serum concentrations.⁶^,⁸⁰^,¹⁷⁴ The lamotrigine/valproic acid combination has been associated with an increased risk of toxic epidermal necrolysis.⁵⁶ The risk of skin rash seems to

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correlate with a high starting dose of lamotrigine and fast dose uptitration when the drug is added to valproic acid. However, Faught et al.⁵⁵ analyzed the incidence of rash in patients who had lamotrigine added to their valproic acid treatment regimen and found that the occurrence of rash was not greater than when lamotrigine was added to other drugs, especially when la-motrigine was titrated up very slowly. Other studies confirmed these findings.¹⁷³ In combination therapy including valproic acid and AEDs with inducing effects, the inhibitory effect of valproic acid on lamotrigine metabolism appears to be stronger than the inducing effects of phenobarbital or carbamazepine on lamotrigine. However, when valproic acid is combined with phenytoin, the effects of both drugs on lamotrigine disposition seem to compensate each other.¹⁰⁶ Decerce et al.⁴² reported that when valproic acid is added to lamotrigine, the greatest impact on the serum level of lamotrigine occurs at dose introduction. In spite of this potentially adverse pharmacokinetic interaction, a favorable pharmacodynamic synergism between valproic acid and lamotrigine was reported by Kanner and Frey.⁸⁰ When valproic acid was added to lamotrigine therapy, a significant reduction in the seizure frequency occurred in patients with refractory epilepsy, resulting in seizure-free patients.⁸⁰ However, recently two cases of lamotrigine toxicity were reported when the drug was coadministered with valproate; the patients developed downbeat nystagmus, and truncal ataxia occurred in conjunction with toxic lamotrigine serum levels.⁵

Drugs used to treat conditions other than epilepsy have also been reported to affect lamotrigine metabolism. The enzyme-inducing agent rifampicin was found to increase lamotrigine clearance by 97%.⁵¹ Oral contraceptives may also increase lamotrigine clearance, and their intake has been associated with a mean 50% decrease in serum lamotrigine levels.¹³¹^,¹⁴² In a study with patients using either no hormonal contraception (n = 18), an ethinylestradiol-containing contraceptive (n = 11), or a progestogen-only contraceptive (n = 16), Reimers et al.¹³¹ demonstrated that it is the ethinylestradiol component that interacts with lamotrigine and not the progestogen. A dose adjustment for lamotrigine might be needed in women taking oral contraceptives.¹⁵⁴

In a parallel, placebo-controlled study in healthy volunteers, coadministration of lamotrigine with olanzapine (5 to 15 mg for 2 weeks) resulted in a small decrease in exposure to lamo-trigine (20% decrease in AUC), suggesting some induction by olanzapine of the glucuronidation pathway of lamotrigine.¹⁵³

Coadministration of acetaminophen enhances the urinary elimination of lamotrigine after single doses of the anticonvulsant (decreases in lamotrigine AUC and serum half-life of 20% and 15%, respectively) when compared to placebo.⁴³

There are two reports of patients who experienced an increase in serum lamotrigine concentration following the addition of sertraline; one patient exhibited toxicity when his lamotrigine levels doubled. The authors suggested inhibition of glucuronidation as a possible mechanism for this interaction.⁸³

Effects of Lamotrigine on the Disposition of Other Drugs.

During repeated treatment, lamotrigine was shown to induce its own metabolism, resulting in a 25% decrease in its half-life. Consistent with this observation, the addition of lamo- trigine to valproate produced a small (25%) but significant decrease in steady-state serum valproic acid concentration. However, the formation clearances of the hepatotoxic valproic acid metabolites 4-ene- and 2(E),4-diene-valproate were unaffected by lamotrigine administration.⁶ Lamotrigine has no significant effect on steady-state concentrations of phenyt-oin, phenobarbital, or primidone.⁷⁶^,⁷⁷^,¹⁰⁰ Increases in serum CBZ-E concentrations and neurotoxicity have been reported following the addition of lamotrigine to a stable drug regimen with carbamazepine.¹⁷¹ However, this observation was not confirmed in other studies,¹⁶^,⁵³^,¹⁰³ suggesting that the interaction with lamotrigine and carbamazepine is pharmacodynamic rather than pharmacokinetic. When pregabalin disposition (600 mg/d for 8 days) was studied in patients taking lamotrigine (100 to 600 mg/d chronically), pregabalin steady-state pharmacokinetic parameters were similar to those found in historical healthy individuals receiving pregabalin alone.²⁵

Although an early study suggested that lamotrigine does not increase ethinylestradiol and levonorgestrel clearances,⁷² a more recent investigation identified a moderate decrease in serum levonorgestrel levels when lamotrigine (300 mg/d) was given to women taking an oral contraceptive.¹⁵⁴ Although in that study intermenstrual bleeding was reported by 32% of women during coadministration of lamotrigine and the oral contraceptive (and follicle-stimulating hormone [FSH] and luteinizing hormone [LH] concentrations were increased by 4.7-fold and 3.4-fold, respectively), the low serum progesterone concentrations suggested that suppression of ovulation was maintained and that oral contraceptive efficacy was not impaired.¹⁵⁴

Oxcarbazepine

Oxcarbazepine is a keto analog of carbamazepine that can be considered as a prodrug because it is rapidly converted to its 10-monohydroxy derivative (MHD), which is primarily responsible for the pharmacologic effect. MHD is metabolized by conjugation with glucuronic acid.⁵⁴ A small proportion (4%) of MHD is oxidized by the CYP system to the inactive 10,11-dihydroxy derivative. More than 95% of a dose is recovered in the urine as follows: <1% as unchanged oxcarbazepine, 49% as inactive glucuronide conjugates of MHD, and 27% as MHD.¹⁶² No autoinduction of metabolism has been observed with oxcarbazepine.

Although structurally similar to carbamazepine, oxcarbazepine is predominantly metabolized by noninducible ketoreductases. However, coadministration of carbamazepine, phenobarbital, or phenytoin decreases the serum concentrations of MHD, probably by inducing its metabolism.¹⁰^,⁷⁴^,¹¹⁰ There is no evidence of a major effect of valproic acid on oxcarbazepine metabolism, and the association with valproic acid should not require any adjustment of oxcarbazepine dose.¹⁰^,¹¹⁰

Several studies evaluated the effects of other drugs on the metabolism and elimination of oxcarbazepine and its major metabolite. In patients comedicated with topiramate, the serum MHD concentration-to-oxcarbazepine dose ratio was not different from that in patients taking oxcarbazepine monotherapy.¹⁰ In the same study this ratio was not altered in patients taking lamotrigine.¹⁰ No significant changes were observed in oxcarbazepine disposition when the drug was concomitantly administered with cimetidine,⁸⁶ dextropropoxyphene,¹¹⁴ erythromycin,⁸⁵ verapamil,⁸⁸ or viloxazine.¹²²

Studies in human liver microsomes showed that oxcarbazepine and its pharmacologically active metabolite MHD have little or no capacity to inhibit the CYP1A, CYP2D, and CYP2E families of isozymes. However, CYP2C19 was significantly inhibited by oxcarbazepine.¹⁶⁵ This inhibition is consistent with the observation of increases in serum phenytoin concentrations up to 40% in patients taking concomitantly oxcarbazepine and phenytoin.⁷⁴ Addition of oxcarbazepine to carbamazepine treatment can lead to a small decrease in serum carbamazepine concentration.¹¹⁰ On the other hand, phenobarbital serum concentrations increased by 14% in patients receiving oxcarbazepine, but this change is not clinically important.⁷⁴

Oxcarbazepine had no effect on the anticoagulant activity of warfarin in ten healthy volunteers.⁸⁹ Coadministration of oxcarbazepine to healthy women receiving oral contraceptives has been associated with 47% and 36% decreases in

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ethinylestradiol and levonorgestrel AUCs, respectively.⁸⁷ When receiving oxcarbazepine with an oral contraceptive, four of six women developed breakthrough bleeding.⁹⁹ Repeated coadministration of oxcarbazepine resulted in a 28% decrease in felodipine AUC and a 34% decrease in felodipine C_max. The reduction in felodipine bioavailability was much smaller than that observed after coadministration of carbamazepine (i.e., 94%).¹⁷⁶ Oxcarbazepine had no effect on androgen levels in men or on pubertal development in girls with epilepsy.¹²⁸ The topiramate concentration-to-dose ratio was not affected by chronic intake of oxcarbazepine.²

In its use as a mood stabilizer, oxcarbazepine caused only minimal and no significant changes in the mean serum levels of risperidone, 9-hydroxy-risperidone, and olanzapine, confirming its weak inducing effect on drug-metabolizing enzymes.¹³⁷

When treatment with carbamazepine is changed to treatment with oxcarbazepine, the serum concentrations of various concurrent drugs might increase because of a decrease in he- patic induction. Leinonen et al.⁹⁰ described two epileptic patients with major depression and panic disorder whose serum citalopram levels increased and antidepressant response changed following the substitution of oxcarbazepine for carbamazepine. Furthermore, seven patients with schizophrenia or organic psychosis had 50% to 200% increases in serum concentrations of haloperidol, chlorpromazine, and clozapine on switching from carbamazepine to oxcarbazepine.¹²⁷^,¹⁶⁴

Tiagabine

Extensive metabolism of tiagabine occurs in the liver and is mediated by CYP3A,¹⁸ with possible contributions from CYP1A2, 2D6, 2C9, 2A6, and 2E1. Only 2% of the dose is excreted unchanged in urine, whereas 25% and 63% of the dose is excreted in urine and feces, respectively, primarily as the 5-oxo and glucuronide metabolites.¹⁷

Concurrent administration of enzyme inducers such as phenytoin, carbamazepine, and phenobarbital reduces considerably tiagabine half-life (which can decrease to 3.8 to 4.9 hours) and accelerates tiagabine clearance (by 50% to 65%).¹³³^,¹⁴⁶^,¹⁵⁸ In contrast, chronic treatment with valproic acid did not have any significant effect on serum tiagabine concentrations in patients.³^,¹³³^,¹⁴⁶^,¹⁵⁸ Concomitant administration with ethanol⁸¹ or triazolam¹³⁴ did not affect tiagabine pharmacokinetics in healthy volunteers. Similarly, interaction studies with theophylline,¹¹¹ digoxin,¹⁵⁷ or warfarin¹¹¹ showed that serum tiagabine concentrations were not changed. Coadministration of cimetidine (800 mg/d) to patients taking tiagabine chronically had no effect on tiagabine pharmacokinetics (Gabitril package insert, Abbott Laboratories). When concomitantly administered, erythromycin, a CYP3A inhibitor, did not significantly affect the C_max, AUC, or half-life of tiagabine.¹⁶³ This lack of effect of erythromycin is unexpected and remains unexplained.

In healthy volunteers, tiagabine treatment did not affect the clearance or the half-life of antipyrine.⁶⁹ In addition, the pharmacokinetics of either carbamazepine or phenytoin is not affected by tiagabine.³^,⁶⁸^,⁶⁹^,⁸¹^,¹¹¹^,¹³⁴^,¹⁴⁶^,¹⁵⁷^,¹⁶³ There was a small decrease in mean valproic acid C_max and AUC during concomitant administration of tiagabine, but this change is not clinically relevant.⁶⁸

In healthy volunteers, administration of tiagabine did not alter the steady-state pharmacokinetics or pharmacodynamics of warfarin,¹¹¹ digoxin,¹⁵⁷ triazolam,¹³⁴ or ethanol.⁸¹

Mengel et al.¹¹² studied the effect of low tiagabine doses (8 mg/d for 12 days) on the pharmacokinetics of oral contraceptives in ten healthy women. Tiagabine did not alter the serum concentrations of ethinylestradiol, levonorgestrel, or desogestrel. Similarly, the levels of progesterone, FSH, and LH did not change with tiagabine therapy. The effects of higher doses of tiagabine on the disposition of oral contraceptives have not been reported.

Topiramate

Topiramate is not extensively metabolized, and 55% to 66% of the dose is eliminated unchanged in the urine.⁴⁷^,⁷⁹^,¹⁵⁰ Six metabolites have been identified in humans and result from hydroxylation, hydrolysis, and glucuronidation. These metabolites are inactive, and the isozymes responsible for their formation have not been characterized.

When concomitantly administered with enzyme-inducing AEDs, the proportion of topiramate metabolized by the liver increases, resulting in a shorter half-life and a higher total clearance. Topiramate dose adjustments might be necessary after discontinuation or addition of enzyme-inducing AEDs such as phenytoin, phenobarbital, and carbamazepine.¹⁹^,⁷⁹^,¹⁴⁴ Recently, the metabolic profile of a topiramate single dose was characterized during induction by carbamazepine (600 mg/d) in 12 healthy individuals. Topiramate remained appreciably excreted unchanged in urine (41%), even though its oral clearance increased twofold. 2,3-O-Des-isopropylidene-topiramate (2,3-diol-TPM) was identified as the most prominent urinary metabolite, with recoveries accounting for 3.2% and 7.9% of the topiramate dose under noninduced and induced conditions, respectively. The AUC(metabolite)/AUC(drug) ratio for 2,3-diol-TPM increased threefold after carbamazepine treatment.²³ Concurrent use of topiramate and valproic acid can result in a slight decrease (15%) in topiramate concentrations.¹³⁹ Two studies reported no change in topiramate pharmacokinetics in patients given fixed-dose lamotrigine therapy.²^,⁴⁸

Topiramate is a weak inducer of CYP enzymes, and, as such, it can decrease ethinylestradiol concentrations at doses >200 mg/d but not at lower doses.⁴⁹^,¹³⁸ There is conflicting evidence on whether 200 mg/d of topiramate also reduces ethinylestradiol levels, but any influence of this dose is likely to be small and of dubious clinical significance.⁴⁹^,¹³⁸ In a single-dose trial with digoxin, topiramate resulted in a small (13%) increase in digoxin clearance.⁹⁷ The effect of multiple dosing with topiramate on the pharmacokinetics of a single dose of haloperidol showed slight increases in haloperidol serum concentrations, although 90% confidence intervals for the ratio of AUC means were within bioequivalence limits.⁴⁸

Topiramate has no major effects on the pharmacokinetics of carbamazepine,¹⁴⁴ primidone, phenobarbital,⁴⁶ or valproic acid.¹³⁹ Similarly, the serum MHD concentration-to-oxcarbazepine dose ratio was not altered in patients taking topiramate compared to a monotherapy group.¹⁰ Coadministration of escalating doses of topiramate in a group of 25 patients resulted in only slight decreases in average serum la- motrigine levels compared with baseline.¹⁴^,⁴⁷ When phenytoin metabolism is at or near saturation, topiramate can increase phenytoin concentrations by 25%,⁶⁰ possibly by inhibiting CYP2C19.⁹³

Zonisamide

Zonisamide undergoes acetylation and reduction to form the N-acetyl and 2-sulfamoylacetylphenol metabolites, respectively. Of the excreted dose, 35% is recovered unchanged, 15% as N-acetyl zonisamide, and 50% as the glucuronide of the 2- sulfamoylacetylphenol metabolite. Reduction of zonisamide is mediated by CYP3A.¹¹⁶ Recently, Mc Jilton et al.¹⁰⁹ reported that some autoinduction of zonisamide metabolism can occur with chronic dosing.

Concurrent medication with enzyme-inducing AEDs increases the metabolism and clearance of zonisamide and shortens its half-life. In patients taking carbamazepine and phenyt- oin, zonisamide half-life was 36.4 and 27.1 hours, respectively, indicating a pronounced effect on zonisamide metabolism.¹¹⁹

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The inducing effects of these drugs on zonisamide metabolism were confirmed by Shinoda et al.,¹⁵² who found that the concomitant administration of zonisamide with phenobarbital, phenytoin, or carbamazepine significantly decreased the ratio of steady-state serum zonisamide concentration to the administered dose (C/D ratio).¹⁵² In that study, clonazepam and valproic acid comedication did not change the zonisamide C/D ratio.

Concurrent administration of cimetidine with zonisamide did not alter zonisamide pharmacokinetics in healthy volunteers.⁶⁷ A lack of interaction between ritonavir and zonisamide has been reported in a patient taking the protease inhibitor concomitantly with carbamazepine and zonisamide: Ritonavir administration resulted in a significant elevation in carbamazepine levels, leading to toxicity, without affecting serum zonisamide levels.⁸² A single case of decrease in serum zonisamide concentrations after coadministration of risperidone in a patient with schizophrenia was reported.¹²⁰ An elevation of serum zonisamide concentration (from a value of 27 to 33 to a value of 61.8 to 64.6 μg/mL) following the addition of lamotrigine was described in two patients receiving stable therapy with zonisamide. One patient also developed signs of zonisamide toxicity after the introduction of lamotrigine.¹⁰⁸

In vitro studies of the inhibitory effects of zonisamide using human liver microsomes showed that zonisamide does not inhibit CYP1A2 and 2D6 and only weakly inhibits CYP2A6, 2C9, 2C19, and 2E1. The estimated K_i for zonisamide inhibition of CYP3A4 was 1076 μM, 12 times higher than the usual therapeutic serum unbound zonisamide concentration.¹²⁶

The potential effects of zonisamide on carbamazepine pharmacokinetics have not been well characterized, with contradictory literature reports: Some authors found no alterations in carbamazepine or CBZ-E levels by zonisa-mide,²⁶^,¹¹³^,¹⁴⁹ whereas others reported a rise in carbamazepine concentration,¹⁴⁵ and others reported a fall in CBZ-E/carbamazepine ratio.¹⁵² Recently, the effect of zonisamide, up to 400 mg/d, on the steady-state pharmacokinetics of carbamazepine and CBZ-E was studied in 18 patients with epilepsy.¹²⁶ The results indicated no statistically significant differences for mean C_max, time to C_max, and AUC_{(0-12 h)} of total and free carbamazepine and CBZ-E measured before and after zonisamide administration. However, CBZ-E renal clearance was significantly (p <.05) reduced. Several studies revealed no significant effects of zonisamide on the serum concentration or protein binding of phenytoin or valproic acid.²⁶^,¹²⁶^,¹⁶⁰ However, in a population pharmacokinetic analysis, a statistically significant increase (16%) in serum phenytoin concentration was observed in patients taking zonisamide.¹¹⁸ This effect was not confirmed in a prospective study designed to measure the effect of the addition of zonisamide (gradually increased to 400 mg/d) on phenytoin pharmacokinetics under steady-state conditions in patients⁹⁶; no significant changes in phenytoin disposition were observed.

Gabapentin, Levetiracetam, Pregabalin, and Vigabatrin

Because gabapentin is not metabolized, interactions via this mechanism are not expected. Indeed, several studies have shown no interaction in either direction with the established AEDs— phenobarbital,⁷⁴ carbamazepine,¹²⁴ valproate,¹²⁴ and phenytoin.³⁷ A statistically significant but clinically irrelevant decrease (14%) in the oral clearance of gabapentin was reported with concurrent use of cimetidine (Product Information for Neurontin, 1999). A case report indicated that the addition of gabapentin to existing therapy with phenytoin, carbamazepine, and clobazam resulted in increased phenytoin levels from 42 to 177 μM, leading to phenytoin toxicity.¹⁶⁶ An increase in serum phenytoin levels following the addition of gabapentin 900 mg daily was also reported by others.³⁷ However, adding gabapentin to single-drug therapy with phenytoin did not significantly affect phenytoin levels.⁸ Hussein et al.⁷⁵ described a pharmacokinetic interaction between gabapentin and felbamate. The study was a large retrospective evaluation in patients taking felbamate alone (n = 40) or felbamate and gabapentin (n = 18); a 50% prolongation of the half-life of felbamate was observed in the patients taking gabapentin.⁷⁵ A mechanism for this effect is not evident. In addition, there is no need to adjust the dose of gabapentin when it is coadministered with levetiracetam.⁵⁸

Levetiracetam is eliminated by renal excretion, with 66% of the dose excreted unchanged and 27% as inactive metabolites. The major metabolic pathway of levetiracetam is an enzymatic hydrolysis of the acetamide group, which is not cytochrome P450 dependent, leading to the inactive metabolite UCB-L057 (24% of dose); two other minor metabolites account for <3% of the dose.¹⁷⁰

Concomitantly administered AEDs do not alter the pharmacokinetic profile of levetiracetam to a clinically important extent. Analysis of serum levetiracetam data obtained during placebo-controlled clinical studies indicated that phenyt- oin, carbamazepine, and phenobarbital can modestly increase levetiracetam clearance by 20% to 30%.³⁵^,¹⁰⁷ Lamotrigine and gabapentin do not influence the pharmacokinetics of levetiracetam.¹²¹ In healthy volunteers, multiple-dose coadministration of valproate did not modify the pharmacokinetic or excretion profile of levetiracetam.²⁷ Likewise, pharmacokinetic parameters of levetiracetam, when it was coadministered with oral contraceptives (Product Information for Keppra), digoxin,⁹⁵ or warfarin,¹²⁶ were comparable to those of individuals receiving levetiracetam alone.

Levetiracetam and its major metabolite were tested for their effects on different drug-metabolizing enzymes in human liver microsomes. An absence of inhibitory effect of levetiracetam on CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4, CYP2A6, UGTs, and epoxide hydrolase was observed.¹¹⁷ Levetiracetam did not modify the pharmacokinetic parameters of phenytoin in healthy individuals²⁷ and in patients.¹²¹ Levetiracetam also had no effect on the serum levels of carbamazepine, valproic acid, phenobarbital, lamotrigine, clobazam. and gabapentin.⁴⁰^,¹²¹^,¹⁵¹ In a similar way, prospective studies with digoxin⁹⁴ and warfarin¹²⁵ indicated that levetiracetam does not affect any of the pharmacokinetic or pharmacodynamic parameters of these drugs. Ethinylestradiol and levonorgestrel pharmacokinetic and pharmacodynamic profiles, assessed during coadministration with levetiracetam for two menstrual cycles, were identical to those observed during coadministration of the contraceptive with placebo.⁶¹

Pregabalin has been approved recently as adjunctive treatment for partial seizures and for the treatment of neuropathic pain. Single- and multiple-dose studies have shown that >90% of a pregabalin dose is recovered unchanged in urine.³⁶ This implies that there is no concern for metabolically based drug interactions affecting pregabalin pharmacokinetics, but there is a need for dose adjustment in patients with renal impairment. A recent study was performed in patients receiving carbamazepine, lamotrigine, phenytoin, and valproate with and without 600 mg/d of pregabalin for 7 days.²⁵ The trough concentrations of these drugs were not affected by pregabalin. Serum pregabalin concentrations in this study were also compared to those of historical controls and no difference was found, implying that these drugs have no effect on the excretion of pregabalin.

Vigabatrin is eliminated essentially unchanged via renal excretion,¹³ and two minor urinary metabolites have been detected in humans.⁵⁰ Coadministration of valproic acid did not produce significant changes in steady-state serum concentrations of vigabatrin in children with refractory epilepsy.⁹ In

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healthy volunteers, felbamate administration for 8 days had no effect on the AUCs of S(+)-vigabatrin and R(-)-vigabatrin.¹²⁹

Several studies have shown that vigabatrin has no significant effect on the serum concentrations of carbamazepine, phenobarbital, primidone, valproic acid, clonazepam, clobazam, ethosuximide, oxcarbazepine, and felbamate.³⁹^,¹⁰²^,¹²⁹^,¹³² However, in another study with 66 patients with epilepsy, vigabatrin was added to carbamazepine therapy, and 69.7% of patients exhibited an increase (at least 10%) in serum carbamazepine concentration. A negative correlation between the increase and the initial level of carbamazepine prior to vigabatrin addition was found, which suggested that the lower the initial carbamazepine level, the higher is the increase in concentration after vigabatrin addition.⁷⁸ Significant decreases in serum phenytoin levels (up to 30%) have been reported in patients receiving vigabatrin as add-on therapy.¹³⁵^,¹³⁶^,¹⁶¹ Serum phenytoin levels generally fall after several weeks of combined therapy, and the mechanism of this interaction has not been elucidated.

Bartoli et al.¹² studied the effect of vigabatrin on in vivo indices of hepatic microsomal enzyme activity and the pharmacokinetics of oral contraceptives in healthy individuals. Results indicated a lack of effect on ethinylestradiol and levonorgestrel disposition and also no effect on hepatic microsomal enzyme activity.¹²

Summary and Conclusions

There is evidence for a few pharmacodynamic interactions, some of which are useful, such as the combinations of valproate with carbamazepine, ethosuximide, phenytoin, and lamotri- gine. Others involve an increase in neurotoxicity, such as that observed when lamotrigine is added to carbamazepine. Most clinically relevant interactions of AEDs are pharmacokinetic. Four established AEDs—carbamazepine, phenytoin, phenobarbital, and primidone—are potent inducers of the cytochrome P450 (CYP450) and UDP-glucuronosyltransferase (UGT) isozymes and affect large series of drugs. By comparison, only three of the new AEDs—felbamate, topiramate, and oxcarbazepine—have mild inducing properties, and this is of concern only in the case of oral contraceptives, for which additional precautions or alternative contraception should be taken. A moderate reduction of the serum levels of levonorgestrel, a progestogen component of oral contraceptives, has also been reported with lamotrigine. Among the new AEDs, felbamate, topiramate, and oxcarbazepine can cause CYP2C19 inhibition and may alter the metabolism of phenytoin.

When considered as substrates, a few new AEDs (felbamate, lamotrigine, tiagabine, topiramate, and zonisamide) are affected by established AEDs with enzyme-inducing properties. However, new AEDs are less sensitive to inhibition by other drugs, only lamotrigine being significantly inhibited by valproic acid. Finally, pregabalin, gabapentin, vigabatrin, and levetiracetam do not present any significant pharmacokinetic interactions with other drugs.

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	Epilepsy: A Comprehensive Textbook 2nd Edition
	© 2008 Lippincott Williams & Wilkins

Epilepsy: A Comprehensive Textbook2nd Edition

Epilepsy: A Comprehensive Textbook
2nd Edition