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Epilepsia, 54(1):1127, 2013

doi: 10.1111/j.1528-1167.2012.03671.x

CRITICAL REVIEW AND INVITED COMMENTARY

Enzyme induction with antiepileptic drugs: Cause for concern?


*Martin J. Brodie, yScott Mintzer, zAlison M. Pack, xBarry E. Gidal,
{Charles J. Vecht, and #Dieter Schmidt

*Epilepsy Unit, Western Infirmary, Glasgow, United Kingdom; yDepartment of Neurology, Thomas Jefferson University, Philadelphia,
Pennsylvania, U.S.A.; zDepartment of Neurology, Columbia University, New York, New York, U.S.A.; xSchool of Pharmacy and
Department of Neurology, University of Wisconsin, Madison, Wisconsin, U.S.A.; {Stichting Epilepsie Instellingen Nederland (SEIN)
Epilepsy Foundation, Heemstede, The Netherlands; and #Epilepsy Research Group, Berlin, Germany

adverse health consequences of these interactions, both


SUMMARY
with AED initiation and withdrawal, remain largely under-
Several commonly prescribed antiepileptic drugs appreciated. Furthermore, induction also affects enzymes
(AEDs)including phenobarbital, phenytoin, and carba- involved in endogenous metabolic pathways, and can alter
mazepinestimulate the synthesis of a broad range of bone biochemistry, gonadal steroids, and lipid markers.
monooxygenase and conjugating enzymes. These agents Therefore, enzyme-inducing AEDs may contribute to the
are well known to reduce the duration and action of many development of a number of comorbidities, including
lipid- and nonlipid-soluble drugs, including anticoagu- osteoporosis, sexual dysfunction, and vascular disease.
lants, cytotoxics, analgesics, antiretrovirals, glucocortic- This process continues as long as the patient takes the
oids, statins, antihypertensives, oral contraceptives, inducer. Modern AEDs that do not possess this property
psychoactive drugs, immunosuppressants, and of course, have similar efficacy for the common epilepsies. Accord-
other AEDs. This process, therefore, may be associated ingly, perhaps consideration should be given to starting
with a number of clinical problems including higher can- treatment with, or even switching patients to, non
cer mortality, progressive AIDS, transplant rejection, and enzyme-inducing AEDs.
unwanted pregnancy. Withdrawal of enzyme-inducing KEY WORDS: Enzyme-inducing antiepileptic drug, Drug
AEDs will increase the concentration of induced drugs, metabolism, Pharmacokinetic interactions, Osteoporo-
bringing with it substantial risk of toxicity if doses are not sis, Sexual dysfunction, Vascular disease.
concomitantly reduced. Yet the potential widespread

The modern treatment of epilepsy began with the discus- metabolism of a range of endogenous substrates is a much
sion of the value of potassium bromide in young women more recent development (Nebert & Russell, 2002). There-
with catamenial epilepsy by Sir Charles Locock in the pages fore, lifelong use of enzyme-inducing AEDs, particularly
of The Lancet in 1857. The next century saw the introduc- phenobarbital, phenytoin, and carbamazepine, has much
tion of phenobarbital, phenytoin, primidone, and ethosuxi- broader implications for the patients general health than
mide. In the 1960s and 1970s, carbamazepine and valproic just the production of pharmacokinetic interactions (Gidal
acid together with the benzodiazepines became available. et al., 2009). Accordingly, it has been suggested that, given
The last 20 years can be regarded as the modern era of the range of effective and well-tolerated AEDs now avail-
antiepileptic drug (AED) development: 15 new agents navi- able, enzyme inducers perhaps should not be regarded as
gated the regulatory hurdles to reach the market. Many of drugs of first choice in newly diagnosed epilepsy (Mintzer
these have been integrated into everyday clinical practice, & Mattson, 2009). This article provides an evidence-based
thereby providing a greater range of options for physicians overview of this potentially important and possibly conten-
and patients (Brodie, 2010). tious pharmacotherapeutic issue.
Enzyme induction was first recognized as a pharmaco-
logic complication of epilepsy treatment >30 years ago
(Perucca, 1978), but awareness of its influence on the
Human Drug Metabolism
Biotransformation of a drug, both in intestinal and hepatic
tissues, is one of the most important determinants of its
Accepted July 30, 2012; Early View publication September 27, 2012.
Address correspondence to Martin J. Brodie, Epilepsy Unit, Western pharmacokinetic profile. Drug metabolism can be broadly
Infirmary, Glasgow G11 6NT, U.K. E-mail: mjb2k@clinmed.gla.ac.uk segregated into two categories: phase I (oxidation, reduc-
Wiley Periodicals, Inc. tion, and hydrolysis) and phase II (conjugation). Oxidative
2012 International League Against Epilepsy biotransformation processes are mediated primarily by the

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M. J. Brodie et al.

cytochrome P450 (CYP) family of enzymes (Nelson et al., the metabolism of the largest number of clinically used
1996), whereas conjugation reactions are conducted largely drugs, as well as a range of endogenous substrates such as
by the enzyme uridine 5-diphospho-glucuronyltransferase prostaglandins, steroid hormones, and fatty acids. CYP2D6
(UGT) (Kiang et al., 2005). The activity of CYP and UGT does not appear to be inducible.
isozymes can be influenced by genetic, environmental In humans, UGTs are expressed as two families in the
(exogenous), and endogenous factors resulting in significant liver and intestine: UGT1 and UGT2. This group of
variation among individuals in drug metabolism. enzymes is also involved in the metabolism of endogenous
Fifteen CYP isozymes, subdivided into three families, are substrates, such as estrogens, progesterone, testosterone,
known to be involved in human drug metabolism (Nelson eicosanoids, bilirubin, thyroxine, bile acids, and arachidonic
et al., 1996). These enzymes are located on endoplasmic acid (Bock, 2010).
reticulum and mitochondrial membranes inside cells.
Although most commonly associated with drug metabolism
in the liver, CYP isozymes are found in a variety of tissues
Mechanisms of Enzyme Induction
including the intestine, kidney, lung, skin, and brain Enzyme induction is mediated through the binding of one
(Pelkonen et al., 2008; Ghosh et al., 2010). In the human or more chemical activators to CYP isozyme intracellular
liver, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 are respon- receptors, ultimately producing increased transcription of
sible for the oxidative metabolism of about 80% of drugs CYP genes. This ligand-activated transcription results in
(Table 1). Among these isozymes, CYP3A4 has the greatest translation of messenger RNA (mRNA) leading to increased
abundance in the liver and intestine, and is responsible for synthesis of the CYP protein. Not all CYP isozymes respond

Table 1. Key cytochrome (CYP) isozymes involved in the metabolism of commonly used drugs
CYP
1A2 2B6 2C8 2C9 2C19 2D6 3A4
Amitriptyline Bupropion Paclitaxel Ibuprofen Lansoprazole Tamoxifen Clarithromycin
Caffeine Cyclophosphamide Repaglinide S-Naproxen Omeprazole Carvedilol Zolpidem
Clomipramine Efavirenz Piroxicam Pantoprazole S-Metoprolol Alprazolam
Clozapine Iphosphamide Glipizide Rabeprazole Timolol Diazepam
Cyclobenzaprine Methadone Losartan Diazepam Amitriptyline Midazolam
Estradiol Irbesartan Phenytoin Clomipramine Triazolam
Fluvoxamine Glyburide Phenobarbitone Desipramine Cyclosporine
Haloperidol Glibenclamide Amitriptyline Fluoxetine Tacrolimus
Imipramine N-DeMe Glipizide Carisoprodol Imipramine Indinavir
Theophylline Amitriptyline Citalopram Paroxetine Ritonavir
Tizanidine Fluoxetine Clomipramine Haloperidol Saquinavir
Verapamil Fluvastatin Clopidogrel Perphenazine Astemizole
R-warfarin Rosiglitazone Cyclophosphamide Risperidone Ziprasidone
Zileuton Tamoxifen Imipramine Thioridazine Amlodipine
Zolmitriptan S-warfarin Nelfinavir Aripiprazole Diltiazem
Progesterone Atomoxetine Felodipine
Propranolol Chlorpheniramine Nifedipine
Teniposide Chlorpromazine Verapamil
R-Warfarin Clonidine Atorvastatin
Codeine Lovastatin
Donepezil Simvastatin
Duloxetine Estradiol
Fluvoxamine Docetaxel
Metoclopramide Progesterone
Nortriptyline Testosterone
Oxycodone Risperidone
Propranolol Aripiprazole
Tramadol Dapsone
Venlafaxine Dexamethasone
Docetaxel
Fentanyl
Haloperidol
Irinotecan
Methadone
Sildenafil

Epilepsia, 54(1):1127, 2013


doi: 10.1111/j.1528-1167.2012.03671.x
13
Enzyme Induction with AEDs

equally to a particular inducer (Table 2). Exposure to a gene transcription (Fig. 1). PXR response elements have
chemical activator may result in a greater degree of induc- been found in human CYP3A4/5, CYP2B6, CYP2C8,
tion in one or more CYP isozymes relative to others (Zhu, CYP2C9, CYP2C19, and CYP1A2 genes and CYP24, a
2010). major enzyme involved in the metabolism of 1,25 (OH)
Although variations in the extent of induction may differ vitamin D3 (Zhou et al., 2006; Tompkins & Wallace, 2007;
between CYPs, there do appear to be common cellular sig- Pelkonen et al., 2008). Induction of CYP3A4 by agents such
naling mechanisms. In general, enzyme induction involves as rifampicin, ritonavir, St Johns Wort, topiramate, ox-
activation of receptor transcription factors such as pregnane carbazepine, phenytoin, and carbamazepine is likely to be
X receptor (PXR), constitutive androstane receptor (CAR), mediated (at least in part) by PXR binding.
and aryl hydrocarbon receptor (AhR) (Tompkins & Wal- Activation of the transcription factor, CAR, may occur
lace, 2007; di Masi et al., 2009). Other nuclear receptors without direct binding to a ligand (Xu et al., 2004), and it is
such as glucocorticoid and estrogen receptors may also par- found primarily in liver and kidney tissue. Similar to PXR,
ticipate in the induction of certain drugs; however, the tran- CAR binds to DNA as a heterodimer with RXR (Fig. 2)
scription factors PXR, CAR, and AhR appear to be broadly (Tompkins & Wallace, 2007). CAR appears to have a smal-
implicated in enzyme induction (Pascussi et al., 2008). ler ligand binding domain than PXR, although CAR and
PXR is not widely distributed, being found primarily in PXR do share some DNA-binding elements, and there is
the liver and small intestine. This receptor contains DNA- some overlap in activating compounds. Experimental
binding and ligand-binding domains. Upon activation, PXR evidence suggests that CAR activation by phenobarbital,
binds to DNA as a heterodimer with retinoid X receptor phenytoin, and carbamazepine is involved in induction of
(RXR) and is translocated to the cell nucleus to regulate CYP1A2, CYP2B6, CYP2C9, and CYP3A4.

Table 2. Enzyme-inducing drugs and their cytochrome (CYP) targets


CYP
1A2 2B6 2C9 2C19 3A4/5
Carbamazepine Carbamazepine Carbamazepine Carbamazepine Carbamazepine
Phenytoin Phenytoin Phenytoin Prednisone Phenytoin
Phenobarbital Phenobarbital Phenobarbital Norethindrone Phenobarbital
Ritonavir Ritonavir Rifampicin Rifampicin Topiramate
Rifampicin Rifampicin St Johns Wort St Johns Wort Oxcarbazepine
Omeprazole Artemisinin Dexamethasone
Polycyclic aromatic hydrocarbons St Johns Wort

Figure 1.
Schematic illustration of PXR
activation by a xenobiotic leading to
CYP3A4 induction. PXR, pregnane
X receptor; PXR-RE, PXR
responsive element; RXR, retinoid
X receptor. Reproduced with
permission from Tompkins and
Wallace (2007).
Epilepsia ILAE

Epilepsia, 54(1):1127, 2013


doi: 10.1111/j.1528-1167.2012.03671.x
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M. J. Brodie et al.

Figure 2.
Schematic illustration of CAR
activation by PB or a CAR agonist
(TCPOBOP). CAR, constitutive
androstane receptor; Hsp90, heat
shock protein 90; CCRP, CAR
cytoplasmic retention protein; PB,
phenobarbital; PP2A, protein
phosphatase 2A; RE, responsive
element; RXR, retinoid X receptor;
TCPOBOP, CAR agonist. Adapted
from di Masi et al., 2009, Copyright
(2009), with permission from
Elsevier.
Epilepsia ILAE

PXR and CAR have not only been shown to increase de phenobarbital. Therefore, pharmacokinetics of the inducing
novo synthesis of CYP protein, but also appear to be impor- drug cannot be ignored. In most cases, however, enzyme
tant in the regulation of genes involved in the expression of turnover will be the rate-limiting step in this process. Evi-
drug transport proteins such as P-glycoprotein (PGP) and dence suggests that CYP3A4 has an enzyme turnover half-
multidrug resistance glycoprotein (MRP). These proteins life of about 3 days and CYP1A2 about 4 days (Magnusson
are constitutively expressed in a variety of organs including et al., 2008). This would imply that maximal induction of
the small intestine, liver, kidney, placenta, and brain. They these important CYPs is likely to take several weeks (Zhu
function as efflux pumps, not only influencing the absorp- et al., 2009), although the onset of induction may be evident
tion and ultimate bioavailability of certain drugs, but in their much sooner (Fleishaker et al., 1995).
eventual tissue distribution. Several drugs, including pheno- In addition to time of exposure, both in vitro and clinical
barbital, carbamazepine, and phenytoin may upregulate studies have demonstrated that the magnitude of induction
PGP expression and activity, thereby reducing the intracell- of various CYP isozymes appears to be at least partially
ular concentrations of substrate drugs (Kim, 2002). dependent upon the dose of the inducing drug (Tomson
Although it is tempting to speculate that induction of drug et al., 1989; Kanebratt & Andersson, 2008). This dose
transporters in the brain may provide an explanation for dependence is seen not only with the older, traditional AEDs
pharmacoresistance in patients with epilepsy, the data such as phenobarbital and carbamazepine, but also with
remain conflicting (Ambroziak et al., 2010). newer agents such as topiramate. Topiramate is frequently
cited as a noninducing medication when, in fact, clinical
Time Course of Induction and studies have shown dose-dependent increases in the clear-
ance of ethinylestradiol in female patients, which are clini-
Deinduction cally relevant at daily doses of 200 mg and above
Unlike enzyme competitive inhibition, enzyme induction (Rosenfeld et al., 1997). In vitro experiments have demon-
is a gradual process. The time required to maximally induce strated concentration-dependent increases in CYP3A4 pro-
an enzyme is governed by the need to either upregulate or tein and mRNA with exposure to topiramate (Nallani et al.,
synthesize new enzyme, assuming that the elimination half- 2003).
life of the inducing drug is less than the enzyme turnover or What happens when an enzyme-inducing drug is discon-
degradation half-life. For example, time to maximal tinued? Deinduction will be related not only to the half-life
induction will be quicker with a short half-life drug such as of the inducer, but also to enzyme degradation rates. At any
rifampicin versus a longer half-life medication such as given time, the amount of drug-metabolizing enzyme is

Epilepsia, 54(1):1127, 2013


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Enzyme Induction with AEDs

regulated by a zero order rate of enzyme production and a antipsychotic drugs is common in patients receiving
first-order rate of enzyme degradation. As discussed previ- enzyme-inducing AEDs, and that this tendency increases
ously, during the process of enzyme induction, enzyme with advancing age (Gidal et al., 2009). As most commonly
amounts are increased either by increasing the rate of used antidepressant and antipsychotic medications are
enzyme production or by stabilization (i.e., decreasing the metabolized by the CYP system, concomitant treatment
rate of degradation). During the process of deinduction, with an inducing AED could lower serum concentrations of,
enzyme amount is decreased (to baseline preinduction lev- for example, tricyclic antidepressants, serotonin-specific
els) by either decreasing production or increasing enzyme reuptake inhibitors, and serotonin and norepinephrine reup-
degradation rate. The turnover half-lives of the particular take inhibitors by as much 2550% (Spina & Perucca, 2002;
enzymes involved, therefore, are the primary parameters Mula, 2008). Enzyme-inducing AEDs have also been
governing the rate at which one can expect resolution of an reported to lower markedly the serum concentration of a
induction type interaction following discontinuation of an number of both typical and atypical antipsychotic medica-
inducing medication. This implies therefore that the time tions (Spina & Perucca, 2002; Besag & Berry, 2006; Botts
course for enzymes to return to baseline or preinduced activ- et al., 2008). The magnitude of this interaction may be quite
ity levels will be gradual. Studies exploring the dissipation pronounced. For example, haloperidol serum concentrations
of increased CYP3A activity following discontinuation of may be reduced by 5060% when taken with carbamaze-
inducers have suggested that this may occur over several pine. Carbamazepine has also been shown to increase sig-
weeks for compounds such as St Johns Wort and rifampicin nificantly the clearance of olanzapine, an antipsychotic drug
(Imai et al., 2008; Reitman et al., 2011). Pharmacokinetic metabolized primarily via CYP1A2 (Lucas et al., 1998). It
modeling following discontinuation of carbamazepine sug- is unclear how often these interactions are clinically rele-
gests a deinduction half-life of approximately 4 days vant. Nonetheless, it would seem reasonable to speculate
(Schaffler et al., 1994). Using an enzyme-turnover model in that individual patients may require increased doses of psy-
patients with epilepsy, Punyawudho et al. (2009) estimated chotropic medication to achieve an optimal therapeutic
that enzyme induction should be reduced by about half at response. Conversely, patients taking a combination of car-
3 days and by 75% at 7 days, and enzyme deinduction bamazepine and an antipsychotic drug are at risk of devel-
would be essentially complete within 2 weeks following oping well-recognized side effects, such as akathisia, when
complete discontinuation of carbamazepine. the former drug is withdrawn, unless the dose of the antipsy-
Deinduction interactions can be particularly insidious. chotic is simultaneously lowered (Strack et al., 2009).
Although a number of pharmacy computer systems and elec-
tronic databases can alert the clinician to potential interac- Chemotherapeutic Agents
tions following the introduction of a potential inducer, there
are no reliable electronic systems to indicate when an offend-
and Cancer
ing drug is removed. Clinicians should be mindful that dis- Numerous studies indicate that concomitant administra-
continuation of a drug is not always within their control, for tion of enzyme-inducing AEDs accelerates the metabolism
instance withdrawal by another doctor or nonadherence to of many classes of chemotherapeutic agents (Table 3)
medication. Only a few days abstinence from carbamazepine resulting in substantially reduced exposure (Vecht et al.,
is likely to produce substantial reduction of enzyme induc- 2003). Approximately one third of patients with cancer,
tion resulting in a commensurate decrease in the metabolism particularly those with brain tumors, are at risk of clinically
of CYP cometabolized medications with an increase in the relevant drugdrug interactions (Riechelmann et al., 2007,
concentration of the induced drug and thereby potential toxicity 2008) that may compromise their survival.
(Strack et al., 2009). These observations would suggest that A number of studies have reported poorer outcomes in
enzyme induction is not merely a yes-no phenomenon, cancer patients receiving enzyme-inducing AEDs. Children
and that the magnitude of an inducing effect may vary even with acute lymphoblastic leukemia had a relapse rate almost
within the same patient depending upon their current dosing three times higher and worse survival associated with faster
regimen and medication-taking behavior. While it is tempt- clearance of teniposide and methotrexate, if they were also
ing to predict de-induction or interaction offset times on receiving enzyme-inducing AEDs (Relling et al., 2000). In
the basis of drug half-lives, this will likely underestimate the patients with glioblastoma multiforme treated with adjuvant
time required for complete dissipation of the interaction. chemotherapy (mainly lomustine), survival was 3 months
shorter for those on concurrent enzyme-inducing compared
Antidepressant and with nonenzyme-inducing AEDs (Oberndorfer et al.,
2005). Use of tipifarnib only led to longer progression-free
Antipsychotic Drugs survival in recurrent malignant glioma among patients who
Psychiatric comorbidities are commonly found in were not receiving an enzyme-inducing AED (Cloughesy
patients with epilepsy (Hoppe & Elger, 2011; Kerr et al., et al., 2006). Combined administration of erlotinib and
2011). Recent studies suggest that use of antidepressant and sirolimus in recurrent glioblastoma resulted in a longer
Epilepsia, 54(1):1127, 2013
doi: 10.1111/j.1528-1167.2012.03671.x
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M. J. Brodie et al.

Table 3. Effect of enzyme-inducing antiepileptic drugs on the pharmacokinetics of chemotherapeutic,


antiretroviral, and immunosuppressive drugs
Number of subjects
Effect of EIAED on
Concomitant drug EIAED(s) concomitant drug Total EIAED No EIAEDa,b,c References
Chemotherapeutic drugs
Busulphan PHT AUC n = 17 n = 9 n = 8a Hassan et al. (1993)
Methotrexate/teniposide CBZ, PHT, PB Clearance n = 182d n = 12 n = 170b Relling et al. (2000)
Paclitaxel EIAEDs MTD n = 24d n = 18 n = 6a Fetell et al. (1997)
Paclitaxel EIAEDs MTD n = 34d n = 27 n = 7b Chang et al. (1998)
Irinotecan CBZ AUC n = 64d n = 52 n = 12b Santisteban et al. (2009)
PHT AUC
Etoposide PHT, PB Clearance n = 29d n = 7 n = 22b Rodman et al. (1994)
Vincristine CBZ, PHT AUC n = 15 n = 9 n = 6a,b,e Villikka et al. (1999)
Tipifarnib EIAEDs AUC n = 47d n = 23 n = 24c Cloughesy et al. (2005)
Erlotinib PB MTD n = 83d n = 53 n = 30c Prados et al. (2006)
AUC
Erlotinib EIAED Clearance n = 32d n = 32 Raizer et al. (2010)
AUC
Gefitinib/sirolimus EIAEDs AUC n = 34d n = 19 n = 15c Reardon et al. (2006)
MTD
Imatinib EIAEDs MTL n = 224d n = 85 n = 28a Pursche et al. (2008)
n = 111b
Temsirolimus PHT AUC n = 36 n = 17 n = 19a Kuhn et al. (2007)
Antiretroviral drugs
Lopinavir/ritonavir PHT AUC n = 24f n = 24 Lim et al. (2004)
Nevirapine EIAEDs t n = 36f n = 32 n = 4a Lhomme et al. (2006)
Efavirenz CBZ t n = 16f Zhu et al. (2009)
Immunosuppressive drugs
Cyclosporin CBZ Steady-state n=6 n=3 n = 3c Cooney et al. (1995)
concentration
Cyclosporin PHT Clearance Animals DSouza et al. (1988)
AUC, area under the plasma concentration-time curve; CBZ, carbamazepine; EIAED, enzyme-inducing antiepileptic drug; MTD, maximum tolerated dose;
MTL, mean through level; PB, phenobarbital; PHT, phenytoin; SN-38, 7-ethyl-10-hydroxy-camptothecin; t, elimination half-life.
= increased; = decreased.
a
Non-EIAED.
b
No anticonvulsants.
c
Not specified.
d
Prospective series.
e
Includes oxcarbazepine.
f
Healthy volunteers.

progression-free survival for patients taking nonenzyme- separately in subgroups of patients who are receiving
inducing AEDs, even if dosing of targeted therapy was cor- enzyme-inducing and nonenzyme-inducing AEDs (Gross-
rected for enzyme induction (Reardon et al., 2010). Concurrent man et al., 1998; Cloughesy et al., 2006; Reardon et al.,
therapy with enzyme-inducing AEDs can also contribute to 2006; Vredenburgh et al., 2007; Puduvalli et al., 2008).
treatment resistance, as chemotherapeutic agents may not Accordingly, the substantial effect that enzyme-inducing
reach sufficiently high concentrations within the target area AEDs can have on the treatment of brain tumors is reflected
because of overexpression of multiple drug-resistance pro- by large differences in the dose regimens of chemotherapeu-
teins (Marini et al., 2007; Lombardo et al., 2008). tic agents, depending on whether or not patients receive an
Studies have also reported higher maximum tolerated enzyme-inducing AED.
doses of chemotherapeutic drugs in patients taking enzyme- Data from prospective phase I/II trials of chemotherapeu-
inducing AEDs (Table 3). This may explain, at least in part, tic drugs stratified according to concomitant use of AEDs
why enzyme-inducing AEDs may lead to a longer survival have clearly demonstrated the powerful enzyme-inducing
in patients with glioblastoma multiforme in some studies properties of phenobarbital, phenytoin, and carbamazepine
(Jaeckle et al., 2009). These data conflict with those from in this setting (Table 3). In principle, anticipated interac-
another retrospective report that patients with glioblastoma tions can potentially be avoided by adjusting the dose of the
taking an enzyme-inducing AED had a shorter survival than chemotherapeutic agent. This course of action requires
those taking an enzyme inhibitor (Oberndorfer et al., 2005). therapeutic drug monitoring of the chemotherapy together
There is agreement that maximum tolerated doses of new with dose adjustment at each change of the AED regimen.
anticancer agents for brain tumors should be determined Harmful drugdrug interactions may be more common than

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Enzyme Induction with AEDs

previously thought, since physicians are often unaware of profiles (increased sex hormonebinding globulin [SHBG],
the potential for drugs to interact. Because metastatic cancer low estradiol, low testosterone, low dehydroepiandroster-
is often associated with a poor prognosis, an inadequate one sulfate [DHEAS]), the potential for sexual dysfunction,
response may be attributed to ineffective therapy rather than as well as increased risk of hormonal contraception failure
to enzyme induction. (Dana-Haeri et al., 1984; Isojarvi, 1990; Murialdo et al.,
1998; Morrell et al., 2001; Galimberti et al., 2005, 2009).
Reduced sex hormone levels may occur secondary to both
Immunosuppressive and enzyme-induced accelerated metabolism and higher SHBG
Antiretroviral Therapy levels, which reduce the bioavailable free concentrations of
reproductive hormones, including estradiol and testosterone
The use of glucocorticosteroids is widespread in medicine,
(Galimberti et al., 2009). Reported changes in sex hormones
including many conditions that require immunosuppressive
secondary to enzyme-inducing AED exposure are supported
therapy or as part of treatment for cancer, in particular pri-
by data from a small prospective study, in which male and
mary brain tumors and brain metastases. Administration of
female patients were tapered off enzyme-inducing AEDs
steroids can easily lead to drugdrug interactions via the
and after 4 months demonstrated significant increases in
CYP3A4 isoenzyme (Li et al., 1995). In this way, enzyme-
inducing drugs can enhance the clearance of steroids; such total testosterone and free androgen index testosterone (Los-
sius et al., 2007).
effects have been shown on coadministration of phenytoin
The clinical relevance of enzyme-inducing AED effects
with dexamethasone (Brophy et al., 1983; Chalk et al., 1984)
on reproductive hormones is demonstrated by reports of sig-
and prednisolone (Frey & Frey, 1984), phenytoin and pheno-
nificant sexual dysfunction in women treated with enzyme-
barbital with methylprednisolone (Stjernholm & Katz, 1975),
inducing AEDs. For example, in a study of 57 reproductive-
or carbamazepine with dexamethasone and other glucocorti-
aged women with epilepsy and 17 controls, women receiv-
costeroids (Spina et al., 1996). Conversely, and, although
ing carbamazepine (n = 12) had lower sexual satisfaction
beyond the scope of this article, dexamethasone may induce
the metabolism of phenytoin with a risk of higher seizure fre- when compared to women treated with lamotrigine (n = 10)
and gabapentin (n = 5) (Morrell et al., 2005). Moreover,
quency. When dexamethasone is discontinued, phenytoin
among women with epilepsy treated with enzyme-inducing
concentrations can easily rise to toxic levels (Lackner, 1991).
AEDs, there were associations between low estrogen and
In addition, dexamethasone may lead to unpredictable inter-
increased sexual anxiety, and low DHEAS and arousal
actions, including both enzyme-inducing and enzyme-inhib-
insufficiency.
iting effects, thus emphasizing the importance of therapeutic
Induced metabolism of sex steroid hormones by AEDs
drug monitoring. The immunosuppressive agents cyclosporin
(Crawford, 2002) potentially increases the risk of contracep-
and tacrolimus are also susceptible to enzyme induction
(Table 3). With concurrent phenytoin, a two to threefold tive failure and breakthrough pregnancy (Kenyon, 1972;
Back et al., 1980; Crawford et al., 1990). This important
higher dose of tacrolimus is needed to maintain desired blood
interaction was well demonstrated by findings from a dou-
levels (Joerger et al., 2004; Wada et al., 2007).
ble-blind, randomized, placebo-controlled, crossover study
The efficacy of antiretroviral drugs such as lopinavir, ri-
of healthy reproductive-aged women (n = 10) treated with
tonavir, nevirapine, and efavirenz may be compromised by
carbamazepine in combination with a commonly used low-
enzyme-inducing AEDs, as shown by pharmacokinetic
dose (20 lg ethinyl estradiol and 100 lg levonorgestrel)
studies in healthy volunteers (Table 3). Monitoring the effi-
oral contraceptive (Davis et al., 2011). Mean area under the
cacy of antiretroviral therapy together with disease activity
is essential when enzyme-inducing AEDs are being con- curve measurements were lower during carbamazepine
cycles compared with placebo for estradiol (p < 0.001) and
comitantly prescribed. Evidence-based guidelines have
levonorgestrel (p = 0.04). Among these women, ovulation
recently been produced on AED selection for people with
occurred in 5 of 10 carbamazepine cycles compared with 1
HIV and AIDS (Birbeck et al., 2012). These recommend
of 10 placebo cycles (p = 0.06) and breakthrough bleeding
that enzyme-inducing AEDs are best avoided in people on
occurred in 8 of 10 carbamazepine cycles compared with 2
regimens that include protease inhibitors or nonnucleoside
of 10 placebo cycles (p = 0.07). Although not consistently
reverse transcriptase inhibitors, as pharmacokinetic interac-
significant (likely secondary to small sample sizes), these
tions can result in virologic failure.
findings suggest that women treated with carbamazepine
using low-dose oral contraceptive hormones are at increased
Reproductive Hormones, risk for decreased levels of contraceptive steroids, increased
Sexual Function, and Oral breakthrough bleeding, and ovulation. If the enrolled
subjects had been treated with a higher dose hormonal
Contraceptives in Women contraceptive pill, the findings likely would have been
Among women with epilepsy, enzyme-inducing AEDs different. It has been recommended repeatedly that women
have been associated with abnormalities in sex hormone using enzyme-inducing AEDs who rely on hormonal
Epilepsia, 54(1):1127, 2013
doi: 10.1111/j.1528-1167.2012.03671.x
18
M. J. Brodie et al.

contraceptives use a higher dose oral contraceptive agent, spe- Most studies evaluating sex steroid hormone profiles in
cifically 50 lg of ethinyl estradiol. In the United States, this men and women treated with enzyme-inducing AEDs were
formulation is available only as emergency contraception. cross-sectional with limited control groups. Although some
The impact of enzyme-inducing AEDs on other hormonal reported abnormalities in sex steroid hormones, with the
forms of contraception including the vaginal ring, contracep- exception of SHBG the findings were not consistent. In
tive patches, and intrauterine devices needs to be clarified. addition, there is a paucity of information on the effect of
newer generation nonenzyme-inducing AEDs on sex ste-
Sexual Function and roid hormones. Well-designed prospective studies, includ-
ing reproductive hormone profiles and clinical outcomes
Fertility in Men such as sexual dysfunction, are urgently required.
Reproductive disorders are more common among men
with epilepsy than in the general population. Enzyme-
inducing AED exposure can contribute to these disorders.
Bone Health
Enzyme-inducing AEDs increase SHBG, thereby decreas- People with epilepsy have an approximately two- to six-
ing free androgens (Isojarvi et al., 1991, 1995; Duncan times greater risk of fracture than the general population
et al., 1999; Verrotti et al., 2011) and DHEAS (Duncan (Pack, 2008). This increased risk is secondary to epilepsy,
et al., 1999). Decreased androgens may result in sexual dys- AED use and, in particular, enzyme-inducing AED expo-
function in some men treated with enzyme-inducing AEDs. sure. A population-based study using the General Practice
For example, Herzog et al. (2005, 2006) studied 85 men Research Database (GPRD) of >40,000 patients with epi-
with epilepsy treated with carbamazepine (n = 25), pheny- lepsy in the United Kingdom found that, after controlling
toin (n = 25), lamotrigine (n = 25), or no AEDs (n = 10) for age and gender, the risk of fracture was about double that
and 25 controls. Sexual dysfunction as demonstrated by in a control group of >80,000 (Souverein et al., 2005). The
lower scores on a standardized sexual function question- impact of AED use on increased fracture risk was demon-
naire was greater in the men treated with carbamazepine strated by findings from a casecontrol study using data
and phenytoin compared with controls as well as men trea- from a Danish hip register (Tsiropoulos et al., 2008), the
ted with lamotrigine. Among men treated with carbamaze- Womens Health Initiative (WHI) study (Carbone et al.,
pine, 32% had scores below the control group and 24% of 2010), and a nested casecontrol study using the GPRD
men treated with phenytoin had scores below the control (Souverein et al., 2006). Enzyme-inducing AED use inde-
group. In contrast, among men using lamotrigine, 4% had pendently increased the risk of fracture in the WHI study as
scores below the control group. SHBG was significantly well as in a Danish-population-based casecontrol study
higher in the carbamazepine and phenytoin groups than in (Vestergaard et al., 2004).
all other groups. Bioactive testosterone levels, bioactive tes- Bone mineral density (BMD) is the most significant pre-
tosterone/bioactive estradiol, and bioactive testosterone/ dictor of fracture, and dual-energy X-ray absorptiometry
luteinizing hormone were significantly lower in the carba- (DXA) is the most studied and understood technique avail-
mazepine and phenytoin groups compared with both the able for its assessment. Using DXA, BMD measurements
control and lamotrigine-treated groups (p < 0.05). Simi- reveal osteopenia or osteoporosis in 3860% of people with
larly, DHEAS was significantly lower in men treated with epilepsy treated with AEDs in specialist epilepsy clinics
carbamazepine and phenytoin compared with controls and (Andress et al., 2002; Farhat et al., 2002). Longer AED use
the lamotrigine group (p < 0.05). This finding supports the was associated with decreased BMD (Sheth et al., 1995;
potential risk of sexual dysfunction in men with epilepsy Andress et al., 2002; Farhat et al., 2002). Enzyme-inducing
treated with enzyme-inducing AEDs, as DHEAS triggers AEDs independently reduced BMD. Their administration
the production of endothelial nitric oxide (Liu & Dillon, was associated with reduced BMD in ambulatory subjects
2002), a signaling molecule that has a role in mediating (El-Hajj et al., 2008). Twins and siblings (<3 years age dif-
erectile function. Fertility may also be affected by potential ference) treated with enzyme-inducing AEDs had lower
adverse effects of phenytoin and carbamazepine on sperm BMD compared with untreated twins and siblings (Petty
(Roste et al., 2003; Isojarvi et al., 2004). Isojarvi et al. et al., 2005). Further support for this observation came from
investigated sperm quality in men with epilepsy treated with findings in a study of previously drug-naive Koreans in
carbamazepine (n = 15) and oxcarbazepine (n = 18) com- whom carbamazepine, but not noninducing AEDs, pro-
pared with controls (n = 41). The frequency of morphologi- duced a significant decrease in BMD (Kim et al., 2007).
cally normal sperm was lower among men treated with both The abnormalities commonly seen in association with
carbamazepine (8%; p < 0.01) and oxcarbazepine (9%; enzyme-inducing AEDs (increased fracture, decreased
p < 0.05) than among controls (14%). Carbamazepine treat- BMD, alterations in bone metabolism) may be directly
ment was also associated with poor motility of sperm related to their hepatic enzyme inducing properties. CYP
(p < 0.05) and low sperm concentrations (p < 0.001) when enzyme induction can lead to accelerated metabolism of
compared with controls. vitamin D to polar inactive metabolites. Animal and human
Epilepsia, 54(1):1127, 2013
doi: 10.1111/j.1528-1167.2012.03671.x
19
Enzyme Induction with AEDs

studies reported that chronic phenobarbital use was associ- (Mintzer et al., 2009). Similar results were obtained when
ated with decreased plasma 3H-labeled vitamin D3 half- patients were switched from enzyme-inducing AEDs to
life and increased biliary excretion of polar metabolites low-dose topiramate (Mintzer et al., 2012) or from carba-
(Hahn et al., 1972; Silver et al., 1974). Liver microsomes mazepine to oxcarbazepine (Isojarvi et al., 1994). These
isolated from phenobarbital-treated animals rapidly con- data suggest a lipid-elevating effect that is specific to the
vert 3H-labeled vitamin D3, 25-hydroxycholecalciferol use of enzyme-inducing AEDs.
and 1,25-dihydroxycholecalciferol into inactive polar Other non-traditional serologic measures appear also
metabolites (Hahn et al., 1972). Reduced active vitamin to be affected by enzyme induction. Lipoprotein(a), an
D leads to decreased intestinal calcium absorption, independent risk factor for cardiovascular disease (CVD),
decreased serum calcium concentration, and compensa- is elevated by carbamazepine (Bramswig et al., 2003),
tory hyperparathyroidism (Pack et al., 2008). Persistent with levels declining by a comparable amount upon
hyperparathyroidism results in increased bone turnover switching to a nonenzyme-inducing AED (Mintzer et al.,
and reduced BMD. Serologic studies revealing low 2009). The inflammatory marker C-reactive protein is ele-
calcium, low active vitamin D metabolites, high bone vated in the epilepsy population (Tan et al., 2009). Patients
turnover markers, and high parathyroid hormone underpin crossing over from carbamazepine or phenytoin to non
this mechanism (Pack et al., 2008). These findings are enzyme-inducing AEDs experienced declines in C-reactive
further supported by studies evaluating the effect of protein of >30% (Mintzer et al., 2009, 2012), indicating
enzyme-inducing AEDs on the expression of specific that a substantial portion of the increase can be attributed
CYP isozymes involved in vitamin D metabolism (Pas- to CYP induction. The prothrombotic amino acid homocy-
cussi et al., 2005; Zhou et al., 2006). steine has been implicated as a risk factor for CVD, stroke,
There are, however, some data contradicting this hypoth- and dementia (McIlroy et al., 2002; Casas et al., 2005;
esis. For example, serum 25-hydroxyvitamin D levels, when Ravaglia et al., 2005). Elevations of homocysteine have
compared among groups of subjects treated with either been found among carbamazepine-treated patients in a
enzyme-inducing AEDs or nonenzyme-inducing AEDs, number of cross-sectional and repeated-measures studies
did not differ in some studies (Stephen et al., 1999; Verrotti (Apeland et al., 2000; Verrotti et al., 2000b; Attilakos
et al., 2000a, 2002; Pack et al., 2005). Others also reported et al., 2006; Belcastro et al., 2010; Linnebank et al.,
evidence of significant osteopenia and increased bone 2011). One recent investigation found no direct effect of
turnover, even though active vitamin D metabolites and carbamazepine, but demonstrated that switching from phe-
parathyroid hormone levels were normal. Moreover, carba- nytoin to a nonenzyme-inducing AED significantly
mazepine may not be consistently associated with decreased reduced homocysteine levels (Mintzer et al., 2009). There-
BMD (Sheth et al., 1995). Further studies are needed to fore, phenytoin and carbamazepine may have different
clarify the mechanisms of enzyme-inducing AED effects on effects on some serologic markers (Lopinto-Khoury &
bone and whether new-generation noninducing AEDs also Mintzer, 2010). These findings could be explained by dif-
impact bone metabolism. ferences in induction profiles between the drugs, but it is
also possible that some of these effects may be due to
Serologic Markers properties other than CYP induction.
Cholesterol synthesis, like most biochemical pathways, is
of Vascular Risk subject to feedback inhibition at the rate limiting step, which
Enzyme-inducing AEDs increase a number of serologic is the action of hydroxymethylglutaryl-coenzyme A (HMG-
markers of vascular risk, particularly cholesterol. Several CoA) reductase. However, this inhibition is not provided by
cross-sectional and repeated-measures studies have demon- the end product, cholesterol, but by a group of oxysterol
strated elevated levels of total cholesterol, low-density lipo- intermediates that are substrates for lanosterol alpha-
protein cholesterol and triglycerides among patients treated desmethylase, an enzyme also known as CYP51A1 (Fig. 3).
with phenobarbital, phenytoin, and carbamazepine relative When rats are given ketoconazole, a potent inhibitor of CYP
to healthy controls (Isojarvi et al., 1993; Verrotti et al., enzymes, the levels of these oxysterol intermediates rise,
1998; Eiris et al., 2000; Bramswig et al., 2003; Nikolaos HMG-CoA reductase activity drops, and production of cho-
et al., 2004; Sonmez et al., 2006; Tomoum et al., 2008; lesterol is reduced (Gibbons, 2002). By analogy, then, one
Chuang et al., 2012). Some of these studies also showed would predict that CYP induction should drive the meta-
increases in high-density lipoprotein cholesterol with carba- bolic pathway forward, reduce the levels of oxysterol inter-
mazepine, although the effect size was somewhat smaller. mediates, reduce feedback inhibition of HMG-CoA
Furthermore, when patients were crossed over from reductase, and increase cholesterol production. This hypoth-
enzyme-inducing AEDs (phenytoin or carbamazepine) to esis fits with the aforementioned clinical data, suggesting
nonenzyme-inducing AEDs (lamotrigine or levetirace- that patients taking enzyme-inducing AEDs (phenytoin or
tam), there was a decrease in total cholesterol averaging carbamazepine) show disturbances of cholesterol (Lopinto-
25 mg/dl, including a decline in most lipid fractions Khoury & Mintzer, 2010).
Epilepsia, 54(1):1127, 2013
doi: 10.1111/j.1528-1167.2012.03671.x
20
M. J. Brodie et al.

Figure 3.
Key steps in the cholesterol
synthesis pathway, highlighting the
role of CYP51A1. HMG-CoA,
hydroxymethylglutaryl-coenzyme A.
Epilepsia ILAE

Vascular Mortality and prior stroke; each found that the incidence of CVD remained
elevated (Annegers et al., 1984; Olesen et al., 2011). There-
Morbidity fore, increased CVD is not restricted to patients with stroke-
The potential importance of these serologic derange- related seizures.
ments can be seen in epidemiologic studies demonstrating CVD may be caused by a number of different pathophysi-
that patients with epilepsy have significantly elevated rates ologic mechanisms. Carotid intima-media thickness is a
of CVD and cerebrovascular disease. Investigations from measure of atherosclerotic diathesis that has been shown to
around the world have shown standardized mortality ratios correlate strongly with the risk of both stroke and myocar-
for CVD (Table 4), which are 1.52.5 times higher in peo- dial infarction in all age groups (OLeary et al., 1999). Four
ple with epilepsy than in the general population (Annegers studies of carotid arteries in patients with epilepsy have
et al., 1984; Nilsson et al., 1997; Ding et al., 2006; Zhu, demonstrated significantly increased intima-media thick-
2010; Mu et al., 2011; Neligan et al., 2011; Olesen et al., ness relative to normal controls (Schwaninger et al., 2000;
2011). Furthermore, two of these studies examined subsets Hamed et al., 2007; Tan et al., 2009; Chuang et al., 2012).
of the epilepsy population, which excluded patients with The most recent of these confirmed that carotid thickness

Table 4. Vascular mortality and morbidity in patients with epilepsy


Study Study size Standardized ratio 95% CI
Neligan et al. (2011) 19,114 person-years IHD mortality: 1.5* 1.12.0
CBVD mortality: 2.9* 2.13.9
Olesen et al. (2011) 213,000 person-yearsa (epilepsy patients CVD mortality: 1.6* 1.61.7
without prior history of stroke) MI morbidity: 1.1* 1.01.2
Stroke morbidity: 2.2* 2.12.4
Mu et al. (2011) 7,000 person-yearsa Cardiac disease mortality: 1.6 0.55.2
CBVD mortality: 1.1 0.43.6
Ding et al. (2006) 5,000 person-yearsa MI mortality: 10.7* 5.695.3
Gaitatzis et al. (2004) 23,000 person-yearsa IHD morbidity: 1.3* 1.21.5
IHD morbidity, age 1664: 1.6* 1.32.0
CVA morbidity: 7.0* 6.47.6
CVA morbidity, age 1664: 14.2* 12.016.7
Nilsson et al. (1997) 53,250 person-years IHD mortality: 2.5* 2.32.7
CBVD mortality: 5.3* 4.95.8
Annegers et al. (1984) Approached 10,000 person-years IHD mortality: 1.2 0.91.5
IHD mortality, age 2544: 5.7* 1.813.3
IHD mortality, age 4564: 2.5* 1.44.1
IHD morbidity: 1.6* 1.22.2
IHD morbidity, idiopathic epilepsy only: 1.5* 1.02.2
CI, confidence interval; IHD, ischemic heart disease; CBVD, cerebrovascular disease; CVD, cardiovascular disease; MI, myocardial infarction; CVA, cerebrovas-
cular accident.
Data marked with an asterisk* are statistically significant (i.e., the lower limit of the 95% CI is 1).
a
Person-years calculated by author of this section of the review (SM), not directly given in study.

Epilepsia, 54(1):1127, 2013


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Enzyme Induction with AEDs

increased with enzyme-inducing AEDs but not with the using only nonenzyme-inducing AEDs, a number of which
noninducer lamotrigine, and that duration of treatment was are now available for the treatment of newly diagnosed epi-
significantly correlated with arterial wall thickness (Chuang lepsy (Glauser et al., 2006). Lamotrigine (Marson et al.,
et al., 2012). These results corroborate the increased CVD 2007) and levetiracetam (Brodie et al., 2007) have efficacy
rates described previously and provide confirmatory evi- and tolerability similar to carbamazepine, and both of these
dence to suggest that CVD in this population is atheroscle- AEDs are recommended in guidelines as first-line treatment
rotic in etiology. options for newly diagnosed focal epilepsy (Perucca &
There have been few direct studies of the effects of individ- Tomson, 2011). In addition, gabapentin, another non
ual AEDs on the development of CVD. A recent study from enzyme-inducing agent, has been included in the American
Denmark found that patients treated with carbamazepine had Academy of Neurology guidelines for treatment of newly
significantly elevated rates of myocardial infarction and diagnosed focal epilepsy (French et al., 2004), although it
stroke relative to those treated with valproate, and signifi- may be less efficacious than carbamazepine for this indica-
cantly higher mortality from CVD than those treated with tion (Marson et al., 2007). For patients with idiopathic gen-
lamotrigine (Olesen et al., 2011). However, the study also eralized epilepsy, nonenzyme-inducing AED options
suggested that death from CVD was even more common include sodium valproate, lamotrigine, and levetiracetam
among patients taking oxcarbazepine or phenobarbital rela- (Perucca & Tomson, 2011). In summary, several non
tive to those taking carbamazepine, which would not be enzyme-inducing AEDs are valid treatment options for
expected if excess CVD were solely linked to CYP induction. newly diagnosed epilepsy. Generic preparations of non
Prior to these observations, the only study of CVD and AEDs enzyme-inducing AEDs have made these treatments less
used a casecontrol design and arrived at the opposite conclu- costly.
sion: that enzyme-inducing AEDs were associated with lower Modern nonenzyme-inducing AEDs may, therefore, be
cardiovascular mortality (Muuronen et al., 1985). This study preferable alternatives to enzyme-inducing AEDs for
was performed in Finland, which is noteworthy because a ser- adjunctive treatment of refractory epilepsy provided they
ies of investigations in that population appeared to demon- have similar efficacy (Mintzer & Mattson, 2009). Although
strate that CYP induction was associated with reductions in there are major differences in the pharmacodynamics of
serum lipids (Luoma et al., 1983, 1985). Clearly, more work enzyme-inducing and nonenzyme-inducing AEDs, and
is needed to clarify these conflicting data. outcome of trials are influenced by study population, design,
and choice of dosages, a meta-analysis has recently shown a
similar responder rate for adjunctive treatment with modern
Cardiovascular Drugs nonenzyme-inducing and enzyme-inducing AEDs (Beyenburg
Most statins are extensively metabolized by the CYP sys- et al., 2012). The risk ratio of responder rates was close to 1,
tem and would be expected to have reduced serum levels in and there was no significant difference in outcome between
the presence of an enzyme inducer. This interaction has enzyme-inducing and nonenzyme-inducing AEDs (0.97;
been directly demonstrated between simvastatin and carba- 95% confidence interval 0.731.29; p = 0.825) (Beyenburg
mazepine (Ucar et al., 2004), and between atorvastatin and et al., 2012).
phenytoin (Bullman et al., 2011). In addition, there is phar- Although a change in medical regimen is standard epi-
macoepidemiologic evidence that patients prescribed lepsy care for patients with uncontrolled seizures or side
enzyme-inducing AEDs required higher doses of statins and effects, there is a lack of class I evidence on the riskbenefit
were more likely to be inadequately treated, indicating that balance of switching from enzyme-inducing to non
this interaction is clinically relevant (Candrilli et al., 2010). enzyme-inducing AEDs. One small randomized study in
Verapamil and many dihydropyridine calcium-channel patients with uncontrolled seizures or side effects on mono-
blockers are extensively metabolized by CYP3A4 and therapy has suggested that switching to lamotrigine was as
CYP3A5 and may be subject to enzyme induction (Spina effective as and better tolerated than carbamazepine or
et al., 1996). There is also extensive interaction between valproate monotherapy (Fakhoury et al., 2004). In a non-
enzyme-inducing AEDs and warfarin, and in the case of randomized study, patients with uncontrolled seizures had a
phenytoin this can be complex, unpredictable, and hazard- slightly, non-significantly higher odds of remission if they
ous (Panegyres & Rischbieth, 1991). remained on the same drug compared to switching to lamo-
trigine, levetiracetam or topiramate monotherapy (1.66;
95% CI 0.368.42; p = 0.532) (Wang et al., 2012). Lim
Clinical Utility of et al. (2009) have suggested in a pilot study that it is safe to
NonEnzyme-Inducing switch patients with occasional seizures or no seizures from
Antiepileptic Drugs phenytoin to levetiracetam monotherapy following craniot-
omy for supratentorial glioma. However, there is currently
Given the range of concerns relating to enzyme induction, no robust evidence to support the contention that switching
it may be worthwhile exploring the riskbenefit balance of to nonenzyme-inducing AEDs in patients with previously
Epilepsia, 54(1):1127, 2013
doi: 10.1111/j.1528-1167.2012.03671.x
22
M. J. Brodie et al.

uncontrolled seizures or side effects is possible without risk- scenarios requiring a switch to a nonenzyme-inducing
ing loss of efficacy or worsening tolerability. Definitive AED, particularly in patients requiring pharmacotherapy for
assessment in double-blind, randomized, controlled trials is cancer. At the very least, people with epilepsy who are
needed (Lim et al., 2009). In addition, well-designed trials established on enzyme-inducing AEDs should be screened
are also required to establish whether the newer non regularly for associated long-term problems, such as osteo-
enzyme-inducing AEDs have detrimental effects on the out- porosis, hyperlipidemia and sexual dysfunction. There
comes of comorbid conditions. should be communication with the patients other care pro-
Switching to another AED (including a nonenzyme- viders regarding the potential for harmful pharmacokinetic
inducing AED) in seizure-free patients seems to carry a sub- interactions. Consideration may be given to switching
stantial risk of relapse. In one small non-randomized study patients to nonenzyme-inducing drugs to avoid these com-
in seizure-free patients who were switched from enzyme- plications, particularly if the epilepsy is not fully controlled.
inducing (carbamazepine, phenytoin) to nonenzyme-indu- For seizure-free patients, careful weighing of the risks and
cing AEDs (lamotrigine, levetiracetam and topiramate), benefits of switching is warranted given the paucity of data
seizure recurrence was reported in 5 (21.7%) of 23 patients regarding its safety. In all such situations, the benefits and
(Wang et al., 2012). Among 46 matched controls, 2 (4.3%) risks of both courses of action should be discussed with the
of 46 had seizure recurrence despite an unchanged regimen patient and his or her family. Nevertheless, the policy of
(odds of seizure recurrence 6.53, 95% CI 1.0261.19, using noninducing AEDs is likely to be cost-effective, since
p = 0.06). Therefore, the risk of seizure recurrence attribu- it avoids the need for higher doses of a wide range of con-
table to AED change was approximately 18% (Wang et al., comitant lipid- and nonlipid-soluble drugs.
2012). However, other studies have convincingly demon-
strated that continued AED treatment does not guarantee
seizure freedom either. Recurrences have been reported in Search Strategy and
as many as 15% of seizure-free patients, despite continued Selection Criteria
AED treatment (Medical Research Council Antiepileptic References for this review were identified by a series of searches
Drug Withdrawal Study Group, 1991; Sillanpaa & Schmidt, of Medline from 1948 to July 2011, Derwent Drug File from 1964 to
2006; Brodie et al., 2012). In seizure-free patients with epi- June 2011, and Embase from 1980 to June 2011. Search terms used
lepsy, any decision to switch from an enzyme-inducing included: enzyme-inducing; antiepileptic drug; anticonvulsant;
AED to a nonenzyme-inducing agent for reasons of poten- UDP-glucuronosyltransferase; glucuronidation induction; aryl
tial comorbidity is difficult to justify based on the available hydrocarbon receptor; pregnane X receptor; drug interaction; immu-
evidence. We need properly designed trials of seizure out- nosuppressant; chemotherapy; cancer; antiretroviral therapy; bone;
come following switching to nonenzyme-inducing AEDs. reproductive hormones; hormones; endocrine; lipids; cholesterol;
C-reactive protein; lipoprotein(a); homocysteine; atherosclerosis;
myocardial infarction; coronary artery disease; stroke; peripheral
Conclusions vascular disease; side-effects; pharmacoeconomics; well-being;
mortality; suicidality. Only articles published in English were
In this article we summarized the available evidence reviewed. The final reference list was selected on the basis of
regarding the potential deleterious effects of long-term relevance to the broad scope of this review.
enzyme induction with AEDs. Furthermore, we have tried
to highlight areas of uncertainty. Clinical problems can
occur due to pharmacokinetic interactions with other medi- Acknowledgments
cations either on introduction of the inducer or due to its UCB Pharma supported the development of this project by bringing the
withdrawal. There is also increasing awareness of endoge- authors together to discuss the format and content of the review. They also
nous, mostly steroid, pathways, relevant in particular to helped to coordinate the initial literature search. A medical writer, Jennifer
Stewart (QXV Communications Ltd, Macclesfield, United Kingdom)
vitamin D and cholesterol metabolism, which are targets for funded by UCB Pharma, was involved in helping with the creation of the
this process. Enzyme induction will continue for as long as manuscript. Her role included coordinating the author review process, pro-
the patient takes the inducer and no-one can predict the duction of original figures, formatting of tables and/or figures, verifying the
accuracy of references, editing and formatting the text, obtaining permis-
health problems that may arise throughout lifes journey. sion statements for copyright-protected material, collecting author contri-
These observations have implications for the general health bution and conflict of interest statements, and assisting with the on-line
of people with epilepsy. submission process by uploading files. All authors prepared, reviewed, and
approved the review for submission. The corresponding author had final
Whether or not enzyme-inducing AEDs should still be responsibility for the decision to submit for publication. UCB Pharma was
used as first-line treatment for newly diagnosed epilepsy, not involved in the production or content of the manuscript.
when many other noninducing, equally effective, alterna-
tives are available, remains a point for discussion. A particu-
lar concern is the possibility that enzyme induction could
Disclosure
contribute to the pandemic of vascular disease (Beaglehole Martin J Brodie serves on scientific advisory boards for Pfizer Inc, UCB
et al., 2011). There are a number of recognized clinical Pharma, Eisai, GlaxoSmithKline, Novartis, Valeant Pharmaceuticals,

Epilepsia, 54(1):1127, 2013


doi: 10.1111/j.1528-1167.2012.03671.x
23
Enzyme Induction with AEDs

Sanofi Aventis, Lundbeck Inc, Neuronex, and Medtronic; has received ble for interindividual variation of UGT levels. Biochem Pharmacol
funding for travel from UCB Pharma; serves as a consultant for Eisai; 80:771777.
serves on speakers bureaus for UCB Pharma, GlaxoSmithKline, Pfizer and Botts S, Diaz FJ, Santoro V, Spina E, Muscatello MR, Cogollo M, Castro
Eisai; and has received research support from UCB, Eisai, and Glaxo- FE, de Leon J. (2008) Estimating the effects of co-medications on
SmithKline. Scott Mintzer has served as a consultant or advisory board plasma olanzapine concentrations by using a mixed model. Prog Neu-
member for Eisai, Sunovion, SK Life Sciences, Supernus Pharmaceuticals, ropsychopharmacol Biol Psychiatry 32:14531458.
Upsher-Smith, and Pfizer; has received payment for lectures from UCB Bramswig S, Sudhop T, Luers C, von Bergmann K, Berthold HK. (2003)
Pharma and GlaxoSmithKline; and receives research support from the Lipoprotein(a) concentration increases during treatment with carba-
National Institutes of Health. Alison M Pack is a member of a Safety and mazepine. Epilepsia 44:457460.
Data Monitoring Board for Pfizer, has received research grants from the Brodie MJ. (2010) Antiepileptic drug therapy the story so far. Seizure
National Institutes of Health, and has received royalties from UpToDate 19:650655.
Inc. Barry E Gidal has received payment for lectures from GlaxoSmith- Brodie MJ, Perucca E, Ryvlin P, Ben-Menachem E, Meencke HJ. (2007)
Kline and UCB Pharma; and serves as a consultant for Upsher-Smith and Comparison of levetiracetam and controlled-release carbamazepine in
Sunovion. Charles J Vecht has received consultancy fees from UCB newly diagnosed epilepsy. Neurology 68:402408.
Pharma; research grants from UCB Pharma, Eisai, and GlaxoSmithKline; Brodie MJ, Barry SJ, Bamagous GA, Norrie JD, Kwan P. (2012) Patterns of
and funding for travel from UCB Pharma. Dieter Schmidt serves on scien- treatment response in newly diagnosed epilepsy. Neurology 78:1548
tific advisory boards for ViroPharma Inc.; has received funding for travel 1554.
from ViroPharma Inc., Sun Pharma, and Novartis; and serves as a consul- Brophy TR, McCafferty J, Tyrer JH, Eadie MJ. (1983) Bioavailability of
tant for ViroPharma Inc., Sun Pharma, and Novartis. We confirm that we oral dexamethasone during high dose steroid therapy in neurological
have read the Journals position on issues involved in ethical publication patients. Eur J Clin Pharmacol 24:103108.
and affirm that this report is consistent with those guidelines. Bullman J, Nicholls A, Van Landingham K, Fleck R, Vuong A, Miller J,
Alexander S, Messenheimer J. (2011) Effects of lamotrigine and phe-
nytoin on the pharmacokinetics of atorvastatin in healthy volunteers.
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