clinical use and monitoring of antiepileptic...

Clinical Use and Monitoring of AntiepilepticDrugs

Claire E. Knezevic1 and Mark A. Marzinke1*

Background: Antiepileptic drugs (AEDs) have been used for the treatment of epilepsy and other neurolog-ical disorders since the late 19th century. There are currently several classes of AEDs available for epilepsymanagement, many of which are also used to treat migraines, bipolar disorder, schizophrenia, depression,and neuropathic pain. Because of their molecular and mechanistic diversity, as well as the potential fordrug–drug interactions, AEDs are prescribed and monitored in a highly personalized manner.Content: This review provides a general overview of the use of AEDs with a focus on the role oftherapeutic drug monitoring. Discussed topics include mechanisms of action, guidelines on the clinicalapplications of AEDs, clinical tests available for AEDmonitoring, and genetic factors known to affect AEDefficacy.Summary: Implementation of AED therapies is highly individualized, with many patient-specific factorsconsidered for drug and dosage selection. Both therapeutic efficacy and target blood concentrations mustbe established for each patient to achieve seizure mitigation or cessation. The use of an AED with anyadditional drug, including other AEDs, requires an evaluation of potential drug–drug interactions. Further-more, AEDs are commonly used for nonepilepsy indications, often in off-label administration to treat neu-rological or psychiatric disorders.

IMPACT STATEMENTUnderstanding the molecular mechanisms of action of antiepileptic drugs, as well as the role of the

clinical laboratory in monitoring drug concentrations, can aid in the successful selection and manage-ment of epilepsy, in its myriad presentations.

1Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD.*Address correspondence to this author at: Department of Pathology, Johns Hopkins University School of Medicine, 1800 Orleans Street,Sheikh Zayed Tower, Room B1-1020G, Baltimore, MD 21287. Fax 410-955-0767; e-mail [email protected]: 10.1373/jalm.2017.023689© 2018 American Association for Clinical Chemistry2Nonstandard abbreviations: ILAE, International League Against Epilepsy; AED, antiepileptic drug; FDA, US Food and Drug Administration;SV2A, synaptic vesicle protein 2A; GABA, γ-aminobutyric acid; GAT-1, GABA-transporter-1; AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropi-onic acid; NMDA, N-methyl-D-aspartate; TDM, therapeutic drug monitoring.3Human genes: CYP2C9, cytochrome P450 family 2 subfamily C member 9; CYP2C19, cytochrome P450 family 2 subfamily C member 19;UGT1A4, UDP glucuronosyltransferase family 1 member A4; UGT2B7, UDP glucuronosyltransferase family 2 member B7; HLA-B, majorhistocompatibility complex, class I, B.

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Epilepsy is a multifactorial neurological disorderthat occurs in 1% of the population and is charac-terized by recurrent and unprovoked seizures. Ep-ilepsies may be generalized (affecting both brainhemispheres) or focal (localized to a single neuralnetwork or hemisphere), and these categories varywith respect to their presentation, severity, and re-sponse to treatment (1). The clinical definition ofepilepsy and diagnostic criteria were updated bythe International League Against Epilepsy (ILAE)2 in2014 (2). A clinical diagnosis of epilepsy may bemade if the following scenarios are met: (a) after 2unprovoked seizures at least 24 h apart, (b) a sin-gle, unprovoked seizure with high risk (>60%) ofrecurrence, or (c) if an individual has been previ-ously diagnosed with an epilepsy syndrome, suchas benign Rolandic epilepsy or Landau–Kleffnersyndrome. Because of themultifactorial etiology ofthe disease, an important consideration in the clin-ical diagnosis of epilepsy is the ability to differenti-ate unprovoked seizures from those triggered byhead trauma, metabolic disturbances, or drug ef-fects; only the former are used in disease diagnosis(3).The use of antiepileptic drugs (AEDs) is the pri-

mary modality for the mitigation of symptoms anddisease management. AEDs are a diverse group ofcompounds with a history reaching back to the1800s. From a historical perspective, potassiumbromide was the first compound used therapeuti-cally for recurrent seizures (4). Although potassiumbromide is no longer standard of care, many tradi-tional compounds, including phenytoin and phe-nobarbital, are still used today (2). AEDs may beadministered as a monotherapy or combinatori-ally, with an overall goal of seizure prevention,while minimizing potential side effects on bothcognition andmood. Currently, there are 24 AEDsapproved by the U.S. Food and Drug Administra-tion (FDA), with the synaptic vesicle 2A (SV2A)ligand brivaracetam most recently approved in2016. A summary of antiepileptic agents, includ-ing their proposed mechanisms of action, is

provided in Table 1. Application of AED therapycan be complex, as a delicate balance must beachieved with respect to efficacy, adverse ef-fects, drug–drug interactions, pharmacogenet-ics, comorbidities, and patient compliance. WithAED therapy, approximately 70% of epilepsy pa-tients achieve full seizure control. Seizures thatdo not respond to AED therapy are consideredrefractory and are treated with a ketogenic diet,stimulation of the vagus nerve, deep brain stim-ulation, or surgery.AED terminology and drug stratification fol-

lows a generational pattern. First-generationAEDs refers to those drugs in use or approvedfor use before 1993; second-generation AEDsare those approved between 1993 and 2007.The most recent AEDs, approved after 2008, arereferred to as third-generation agents. Whilethird-generation AEDs elicit their effects via a va-riety of mechanisms, these compounds exhibitimproved bioavailability, lower plasma proteinbinding (with the exception of clobazam, ezogabine,and perampanel), and fewer drug–drug interac-tions than first- and second-generation com-pounds(5).The physiological underpinning of epilepsy is a

misfiring of neurons in the brain. Neuronal sig-naling is based on the propagation of actionpotentials down a neuronal axon, ultimately re-sulting in the release of neurotransmitters fromthe presynaptic neuron into the synaptic junc-tion (Fig. 1). Once released, neurotransmittersbind to receptors on the postsynaptic neuronalmembrane, allowing for signal propagation tothe postsynaptic cell. Seizures result from eitherexcess neuronal excitation or amelioration of neuro-nal inhibition. AEDs primarily function bymodulatingneurotransmitter activity to prevent inappropriatesignaling. However, these compounds may alsocause sedative effects and pain relief, resulting inAED utilization in clinicopathological states otherthan epilepsy.

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Table1.

FDAap

provalyearsan

dmolecular

mecha

nism

sof

antiep

ilepticdrug

s.

Drug

Year

offirstFD

Aap

proval

aAED

gene

ration

Therap

eutic

rang

e(μg/mL)

Liveren

zyme(s)respon

sible

formetab

olism

Voltage-gated

sodium

chan

nel

inhibition

GABA

-related

mecha

nism

s

AMPA

receptor

antagonist

Other

mecha

nism

sPhenobarbital

Pre-FD

AFirst

15–40

CYP2C9,CYP2C19

XX

Primidone

1954

First

5–12

CYP2C19

XX

Phenytoin

1953

First

10–20

CYP2C9,CYP2C19

XEthosuximide

1960

First

40–100

CYP3A4

Ca+2channel

inhibitor

Carbam

azepine

1968

First

4–12

CYP3A4

XClonazepam

1975

First

0.02–0.07

CYP3A

XValproicacid

1978

First

50–100

CYP2A6,CYP2B6,CYP2C8/9,

CYP2C19,CYP2E1

XX

NMDAsignal

inhibition

Gabapentin

1993

Second

12–20

Nohepatic

metabolism

XFelbam

ate

1993

Second

30–60

CYP3A4,CYP2E1

XNMDAsignal

inhibition

Lamotrigine

1994

Second

3–15

Glucuronidation

XX

Topiramate

1996

Second

5–20

Nosignificanthepatic

metabolism

XX

XTiagabine

1997

Second

0.005–0.07

CYP3A

XLevetiracetam

1999

Second

10–60

Nohepatic

metabolism

SV2A

ligand

Oxcarbazepine

2000

Second

12–35

ARK1C1,ARK1C2,ARK1C3,ARK1C4

XZonisamide

2000

Second

10–40

CYP3A4

XX

XPregabalin

2004

Second

2–5

Nohepatic

metabolism

Ca+2channel

inhibitor

Rufinam

ide

2008

Third

5–30

Hum

ancarboxylesterase

1(hCE1)

XLacosamide

2008

Third

1–10

cCYP2C19

XCR

MP2i

Vigabatrin

2009

Third

20–160

cNosignificanthepatic

metabolism

XRetigabineb

2011

Third

NAd

glucuronidated

K+channel

stimulation

Clobazam

2011

Third

0.03–0.3

CYP3A4,CYP2C19,CYP2B6

XPerampanel

2012

Third

NAd

CYP3A4

XEslicarbazepine

2013

Third

3–35

glucuronidated

XBrivaracetam

2016

Third

NAd

CYP2C19

SV2A

ligand

aReferenceforFDAapprovaldates:Drugs@FD

Adatabase.

bDiscontinuedas

ofJune

2017

forcom

mercialreasons.

cTherapeutic

ranges

arenotw

ellestablished;usuallevelsundern

ormaldosing

show

n.dNotherapeutic

rangedeterm

ined.

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Mechanisms of action of AED drug classes

AEDs can be stratified by their molecular mech-anisms of action (Table 1). However, there are sev-eral AEDs in which the mechanism of action is notestablished or only partially elucidated. Eachdrug's mechanism of action can target specific sei-zure subtypes and other disease states that maybenefit from the compound, including the man-agement of pain.Many of the traditional AEDs, including carbam-

azepine and phenytoin, elicit their mechanisms ofaction through the inhibition of voltage-gated so-dium channels. These channels serve as criticalcomponents for the initiation and propagation ofaction potentials, facilitating neurotransmitter re-lease and signal transmission to postsynaptic neu-rons. Voltage-gated channel inhibitors may exerttheir effects through stabilization of the channel inthe inactive state via transient interactions with thecore ormembrane-bound portions of the channel.Certain AEDs are postulated to function solelythrough this mechanism, while several combinethis activity with other molecular mechanisms tomodulate neurotransmission.

Compounds like lamotrigineandvalproicacidelicittheir antiepileptic activity through several mecha-nisms, all related to the action of the inhibitory neu-rotransmitter, γ-aminobutyric acid (GABA). GABAserves to prevent the generation of action potentialsat thepostsynaptic neuronand is regulatedby trans-porter protein GABA-transporter-1, or GAT-1 (6).GAT-1 facilitates GABA reuptake into the presynapticneuron for degradation. The GABAA receptor is a li-gand-gated chloride channel that, when activated byGABA or another small molecule, hyperpolarizes themembrane, thereby suppressing action potentials inthe postsynaptic neuron. Several AEDs, includingphenobarbital, clonazepam, felbamate, and topira-mate, are known to activate the GABAA receptor.Others, such as tiagabine and vigabatrin, inhibitGABA reuptake or degradation, thus prolonging GA-BA's inhibitory effect on neurotransmission. Addi-tionally, gabapentin is structurally similar to GABA,and stimulates GABA release throughmultiple inter-actions, one of which may be inhibition of voltage-gated calcium channels (7).Several other molecular mechanisms are used

by AEDs that target a diverse set of proteinsand processes. Levetiracetam and its recently

Fig. 1. Overview of neurotransmitter activity at the pre- and postsynaptic junction.Postsynaptic potentials result from the presynaptic release of neurotransmitters into the synaptic cleft.


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approved chemical analog brivaracetam arethought to exert their effects through binding toSV2A, a neurotransmitter reporter found in synap-tic vesicles and endocrine granules. SV2A wasshown to regulate the exocytotic release of GABA(8). Thus, these drugs may be similar to those withGABA-related mechanisms. Notably, both leveti-racetam and brivaracetam have improved toxicityprofiles compared with earlier generation AEDs.Phenobarbital, topiramate, and zonisamide par-tially elicit their antiepileptic functions by operatingas competitive antagonists of the glutamate-gatedα-amino-3-hydroxy-5-methyl-4-isoxazolepropionicacid (AMPA) receptor. AMPA receptors are ligand-gated ion channels that mediate fast excitatoryneurotransmission. Further, the primary mecha-nism of action of third-generation AED peram-panel is through the noncompetitive antagonismof the AMPA receptor. Valproic acid and felbamateare both thought to combine a GABA-relatedmechanism and N-methyl-D-aspartate (NMDA)signal inhibition. NMDA is an agonist of the NMDAreceptor, which is a postsynaptic glutamate recep-tor involved in the regulation of synaptic plasticity.NMDA receptor hypofunction and overstimulationhave been implicated in a wide range of neurolog-ical disorders, including dementia, neuropathicpain, schizophrenia, and epilepsy (9).

Epilepsy treatment guidelines

Major epilepsy groups have published andcontinue to update clinical guidelines for the di-agnosis and treatment of epilepsy. These includethe American Academy of Neurology, theAmerican Epilepsy Society, and the ILAE. In 2015,the American Academy of Neurology andAmerican Epilepsy Society published a joint guid-ance based on a systematic review of 47 qualifyingstudies on the treatment of adults with a first un-provoked seizure (10). This meta-analysis revealedthat the overall risk for seizure recurrence within 2years was 21%–45% and that certain clinical char-acteristics were linked with an increased risk of

seizure recurrence, including electroencephalo-gram with epileptiform abnormalities, abnormalbrain imaging, prior brain insult, and nocturnal sei-zure. Immediate initiation of AED therapy reducedthe risk of recurrence by 35% within the first 2years when compared with delaying AED therapyuntil a second seizure event. In these studies, thefirst-generation AEDs carbamazepine, phenytoin,and phenobarbital were most often used. How-ever, no difference in quality of life or rate of long-term (2–5 years) seizure remission was foundbetween immediate and delayed AED therapy ini-tiation. While the rate of adverse events fromAEDs, including depression, dizziness, GI symp-toms, fatigue, and headache, was as high as 31%,most adverse events were mild and reversiblethrough dose reductions. These findings suggestthat therapeutic drug monitoring (TDM) may bebeneficial to ensure sufficient exposure and mini-mize toxicities, thereby increasing efficacy andquality of life regardless of whenpharmacotherapyis initiated.Althoughmost clinical trials and guidelines focus

on epilepsy in adult populations, children accountfor roughly one-quarter of all epilepsy cases. Theguidelines published in 2003 by the AmericanAcademy of Neurology and the Practice Commit-tee of the Child Neurology Society provide similarrecommendations for children as those providedfor adults (11). An important consideration in theinitiation of daily pharmacotherapy in a pediatricpopulation is the potential impact of drug admin-istration on the child's psychosocial development.Although fewer trials have been conducted inpediatric populations, the effects of AED therapyare similar in children as in adults. AED therapylikely reduces the risk of a second seizure, but itdoes not necessarily improve long-term remis-sion success.A survey of clinical trials evaluating the efficacy of

AEDs for various types of epilepsy was first pub-lished by the ILAE in 2006 (12) and updated in 2013(13). Notably, data were enriched and recommen-


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dations made primarily for focal seizures andpediatric absence seizures. For other epilepsytypes, such as generalized onset tonic-clonic andjuvenile myoclonic epilepsy, only low levels of evi-dence were available. Overall, well-designed ran-domized controlled trials are lacking in epilepsy,and this makes it difficult to determine which AEDsare the most effective for each type of epilepsy. Assuch, empirical use of AEDs is necessary when rec-ommended first-line drugs are not effective andliterature data are limited.

AED therapy

The goals for AED therapy postdiagnosis are toprevent further seizures while minimizing adverseand off-target drug effects. Generally, AED mono-therapy is initiated and patient response is moni-tored. If seizure control is not achieved initially,monotherapy is attempted with a different AED.Transitioning between monotherapies requiresvigilant monitoring for efficacy and potential toxic-ity. Approximately 50% of patients achieve seizurecontrol with monotherapy (14). Once mono-therapy options have been exhausted, combina-tion therapy with an adjunctive AED is commonlypursued for disease management. Of note, manyof the second- and third-generation AEDs were ini-tially approved as adjunctive therapies; however,recent data suggest that many of the third-generation AEDs are also effective as first-linemonotherapies (15, 16). While these drugs may bepreferred by patients due to a lower incidence ofside effects, most are not currently approved asfirst-line therapies for epilepsy.Given the large number of drugs and overlap-

ping mechanisms of action within drug classes,AED selection can be a significant challenge. Cur-rent guidelines in the US and Europe providemultiple options for first-line, second-line, and ad-junctive therapeutic options for each type of sei-zure, as outlined in Table 2 (17). There are manykey factors that must be considered when select-ing a therapy, either for initial or combination ther-

apy, all of which are specific to the patient (18).These include (a) the demonstrated efficacy ofeach drug toward the specific type of seizure; (b)potential side effects of the drugs, especially withregard to the patient's preferences; (c) hepatic andrenal function; (d) use of concurrent medications,including oral contraceptives; (e) reproductiveplans, as some drugs may adversely affect fertilityand/or fetal development; and (f) the cost of thetherapeutic agent, with respect to insurance cov-erage as older therapies are available as lower costgenerics, while newer drugs are still on patent andmay be significantly more expensive.Addition of an adjunctive AED, or incorpora-

tion of an AED into an existing drug regimen,requires an assessment of potential drug–druginteractions. This topic is beyond the scope ofthis review, and reference texts are availablethat enumerate the many AED drug–drug inter-actions that have been established and ob-served (19, 20). In brief, most AEDs are at leastpartially metabolized by liver enzymes, andmanyAEDs either inhibit or induce hepatic cyto-chrome P450 enzyme activity. Drug doses mustbe carefully selected and adjusted to achieve de-sired therapeutic concentrations.

Therapeutic drug monitoring for AEDs

The importance of monitoring AED concentra-tions in blood has been recognized for several de-cades. AEDs have a narrow therapeutic windowand display wide interindividual variability with re-gard to pharmacokinetics. One challenging aspectof AED therapy is that their clinical efficacy is vari-able, even among patients with the same serumdrug concentrations. Given these considerationsand the common use of multiple AEDs, TDM is animportant aspect of pharmacological epilepsytreatment. Guidelines concerning the use of TDMfor AEDs were first published by the ILAE in 1993(21) and updated in 2008 (22). The ILAE empha-sized the thoughtful application of TDM and use ofTDM results within the larger clinical context


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Table2.

Recommen

dedan

tiep

ilepticdrug

s(first-lin

e,ad

juvant,and

second

ary)by

seizuretype

.

Seizuretype

Presen

tation

First-lin

edrug

option

sAdjuv

antdrug

option

sFu

rthe

rdrug

option

sDrugs

that

may

worsen

seizure

Generalized

tonic-

clonic

Initialgeneralm

uscle

stiffening,then

jerkingoflim

bsina

rhythm

icpattern.

Carbam

azepine,lamotrigine,

oxcarbazepine,valproic

acid

Clobazam

,lam

otrigine,

levetiracetam

,valproicacid,

topiramate

NA

Gabapentin,phenytoin,

pregabalin,tiagabine,

vigabatrin

Tonicor

atonic

Tonic:sudden

and

generalstiffening

ofmuscles,usuallyfor

abouta

minute.

Atonic:suddenloss

ofmuscletone.

ValproicAcid

Lamotrigine

Rufinam

ide,topiramate

Carbam

azepine,gabapentin,

oxcarbazepine,pregabalin,

tiagabine,vigabatrin

Absence

Seizurewith

arrestof

currentbehavior

with

EEGshow

ing

generalized

spike

waveactivity.

Ethosuximide,lamotrigine,

valproicacid

Ethosuximide,

lamotrigine,valproic

acid

Clobazam

,clonazepam,

levetiracetam

,topiramate,

zonisamide

Carbam

azepine,gabapentin,

oxcarbazepine,phenytoin,


vigabatrin

Myoclonic

Veryshortand

sudden

jerking

movem

ents.

Levetiracetam

,valproicacid,

topiramate

Levetiracetam

,valproic

acid,topiramate

Clobazam

,clonazepam,

piracetam,zonisam

ide

Carbam

azepine,gabapentin,



vigabatrin

Focal

Seizureislim

itedto

onehemisphere,

canbe

localized

orwidelydistrib

uted.

Carbam

azepine,lamotrigine,

levetiracetam

,oxcarbazepine,valproic

acid

Carbam

azepine,

clobazam

,gabapentin,

lamotrigine,

levetiracetam

,oxcarbazepine,

topiramate,valproic

acid

Eslicarbazepine,lacosam

ide,

phenobarbital,phenytoin,


vigabatrin,zonisam

ide

NA

Juvenilemyoclonic

epilepsy

Myoclonicseizures

afterw

aking,with

onsetbetween5–

20yearsofage.

May

also

have

absenceand

generalized

tonic-

clonicseizures.

Lamotrigine,levetiracetam

,topiramate,valproicacid

Lamotrigine,

levetiracetam

,topiramate,valproic

acid

Clobazam

,clonazepam,

zonisamide

Carbam

azepine,gabapentin,



vigabatrin


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to guide dosage changes. In particular, theyrecommended establishing a patient-specific ef-fective range, termed the therapeutic range, afterAED therapy is initiated, and assessing drug con-centrations every 6–12 months or when changesto the clinical situation warranted. In contrast tothe individualized therapeutic range, the commis-sion defined the term “reference range” as a pop-ulation-based effective range established by eachlaboratory. Lamotrigine is a widely used AED andserves as a good example for how TDM for AEDs ispracticed in the clinic. As with many AEDs, there isno established target range, but a general sug-gested reference range of 3–15 μg/mL is widelyused. While a higher rate of mild to moderatetoxicities is observed at concentrations above 15μg/mL, some patients achieve effective seizureprevention without adverse effects at these lev-els, demonstrating the need to establish individ-ual therapeutic target concentrations (23).To date, only 2 published randomized trials have

compared epilepsy patients with and without rou-tine TDM for guiding AED dosing. Neither trialfound an improvement in overall outcome withroutine TDM (24, 25). These results do not, how-ever, address the utility of TDM in selected clinicalsituations, such as during medication modifica-tions, in which the information provided is likelymore impactful. Further, the need for TDMof third-generation AEDs has not been definitively estab-lished and may thus be used in a different contextthan for first- or second-generation AEDs.Due to short half-lives, many AEDs are associ-

ated with a high pill burden to sustain therapeu-tic concentrations. For some second-generationAEDs, extended-release formulations have beenapproved and marketed for epilepsy and other in-dications. These include gabapentin, lamotrigine,levetiracetam, oxcarbazepine, and topiramate. Re-views of available pharmacokinetic data suggestthat the overall PK data for extended-release for-mulations compares favorably to immediate-release formulations, with reductions in peak-to-

trough fluctuations (26). Although small studieshave shown that patients rate tolerability and qual-ity of life higher when switched to extended-release formulations, there is no large-scale evi-dence of increased safety (26, 27). The potentialadvantages of once-daily administration includeincreased compliance, more stable blood concen-trations, and patient preference for more conve-nient dosing.Although AEDs elicit their mechanisms of action

in the non-protein bound, or free, form, laboratoryassays typically report total drug concentrations inserum or plasma. Free drug measurements arenot indicated or clinically useful for non-highlybound molecules, such as phenobarbital. How-ever, when a molecule is highly protein bound,such as is the case with phenytoin, measurementof free drug concentrations can provide additionalinformation regarding therapeutic efficacy or tox-icity. Anemia, hypoalbuminemia, and uremia canall displace drug–protein interactions, thereby in-creasing free drug concentrations. Thus, for highlyprotein-bound AEDs, when plasma protein con-centrations are altered, such as during pregnancy,or low, such as in elderly patients, free drug mea-surements can be clinically useful for drug moni-toring (28, 29). Non-protein bound drug may beseparated using methodologies such as ultrafiltra-tion before analysis with downstream laboratorymethods.

Analytical methodologies

Immunoassays. Immunoassays are commonlyemployed in the measurement of many first-generation AEDs. While many vendors have au-tomated antibody-based assays available forcanonical AEDs like phenytoin and carbamaz-epine, immunoassay offerings for many second-and third-generation compounds are morelimited. Of note, QMSTM Therapeutic DrugMonitoring via Thermo Fisher Scientific and ARKDiagnostics offer microparticle or enzyme-


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based immunoassays for AED quantification,respectively. Homogeneous immunoassays areavailable for second-generation AEDs, includinglamotrigine (30), levetiracetam (31), gabapentin(32), topiramate (33), and zonisamide (34). Offer-ings via third-party vendors, such as theaforementioned assays available through ARKDiagnostics, may be integrated into automatedlaboratory platforms to streamline laboratorywork flows. Important considerations, however, in-clude potential increased cost per assay and de-creasedefficiencydue to limited reagent stability andlaboratory needs. Further, like all immunoassays,they can be subject to interferences and cross-reac-tivity with similar compounds.

Mass spectrometry

In the absence of commercially available meth-ods for all AEDs, mass spectrometry is an alterna-tive approach for AED quantification. Notably, theuse of liquid chromatography-mass spectrometry(LC-MS/MS) provides an additional level of analyteidentification and can differentiate similar com-pounds based on fragmentation of the analyte anddetection of the resulting product ions. Such labo-ratory tests may be targeted for a single AED ormay be multiplexed in design. In the literature,there are a plethora of methods described for thequantification of individual AEDs in biological ma-trices, with the majority of these methods utilizingmass spectrometry. Of note are several publica-tions describing multiplexed LC-MS/MS methodsfor the identification and quantification of 10 ormore AEDs within a single analytical run (35–39).Simultaneous quantification of analytes is chal-lenging due to the potential for similar retentiontimes, variable ionization efficiency, and overlap-ping precursor and product ions. Nonetheless,published methods demonstrate that 10–12AEDs, generally including first- and second-generation drugs, can be successfully quantifiedusing as little as 10 μL of plasma or serum (35, 38,39). Chromatographic times varied from 6–12 min

(35, 38, 39). Up to 22 AEDs can be successfullyquantified with 100 μL of material, including manynewer AEDs.With an increasednumber of drugs toseparate, analytical run times may exceed 17 minper sample (36, 37). Most patients on multi-AEDtherapy are prescribed 2 or 3 AEDs at a time, andthese combinations are tailored to the individualpatient. If developed for clinical use, a multiplexedassay covering most AEDs could be applied tonearly all patients and reduce the number of sep-arate tests ordered. Further, specialized laborato-ries may provide quantitative tests for AED TDMutilizing immunoassay, gas chromatography(GC), high-performance liquid chromatography(HPLC), or LC-MS/MS technologies, with multiplemethods potentially available for the same AED.When potential interferences with an immunoas-say are of concern, methodologies that utilizechromatography could be used, as these providephysical separation of serum components.

Use of AEDs in nonepileptic disease states

While AEDs are developed and studied for theirability to address epilepsy, they are also commonlyused for other indications. In fact, the majority ofAEDs are prescribed to patients without an epi-lepsy diagnosis, mostly for the treatment of psychi-atric disorders (40, 41). While the use of AEDs inpsychiatric disorders is widespread, only 4 AEDsare approved by the FDA for psychiatric indications(pregabalin for generalized anxiety disorder andcarbamazepine, lamotrigine, and valproic acid forbipolar disorder). Beyond this small number ofdrugs and limited indications, the use of AEDs inpsychiatric disorders is considered off-label.Support and guidance for how AEDs can be usedis derived mainly from open-label studies, smalluncontrolled trials, and case reports (42). Addi-tionally, the incidence of psychiatric disorders,particularly depression, among patients with ep-ilepsy is higher than that of the general popula-tion and thus appropriate AED therapy may beused to treat both conditions (43).


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Other common indications for AED use are neu-ropathic pain and headaches. Gabapentin andpregabalin are approved for postherpetic neural-gia (lingering pain from complications of shingles),while pregabalin is also approved for the treat-ment of peripheral diabetic neuralgia. Gabapentinand pregabalin generally provide a 30%–50% re-duction in pain, although side effects of dizziness,somnolence, and weight gain are common (44).Carbamazepine is the first-line treatment for tri-geminal neuralgia (severe episodic facial pain);however, the progressive nature of the diseasedecreases carbamazepine's effectiveness overtime (45). The Canadian Pain Society recentlyrecommended gabapentin, pregabalin, and car-bamazepine as first-line therapies and otheranticonvulsants as fourth-line therapies for neu-ropathic pain (46).AEDs are used for pain relief from headaches,

particularly migraine headaches. While bothtopiramate and valproic acid are approved forthe treatment of migraines, several other AEDs,such as carbamazepine, clonazepam, levetirac-etam, vigabatrin, and zonisamide, are commonlyprescribed off-label for this purpose (47). Unfor-tunately, clinical data for most AEDs for the pre-vention of migraines are limited. The best clinicalevidence is available for topiramate and valproicacid, both of which reduce migraine frequencywhen compared with placebo in multiple clinicaltrials (48).

Genetic variables in drug metabolism

Several polymorphisms are known to havepharmacogenetic effects for one or moreAEDs. These effects include alterations to phar-macokinetic parameters and increased riskof serious adverse effects. Within the HLA-B15serotype, one polymorphism has been identifiedthat increases the risk of certain severe adverseeffects of some AEDs. HLA-B*1502 has beendemonstrated to increase risk for Stevens–Johnson syndrome, a condition of blistering and

peeling of the skin, due to treatment with carba-mazepine, oxcarbazepine, phenytoin, and lam-otrigine. The link between HLA-B*1502 andincreased risk of Stevens-Johnson syndrome hasbeen most strongly observed among the HanChinese and Thai populations and occurs to alesser extent in Caucasian populations, suggest-ing that other factors modulate the penetranceof this polymorphism (49).Cytochrome P450 (CYP) enzymes are respon-

sible for the oxidation processes of phase I me-tabolism. CYP2C93 polymorphisms have beendemonstrated to decrease the rate of metabolismof phenobarbital, phenytoin, and valproic acid (49).This effect is most pronounced for phenytoin,where CYP2C9 is responsible for 90% of metabo-lism. Despite high-quality evidence, prospectiveCYP2C9 genotyping is not commonly performed,with clinical practice generally relying on monitor-ing serumdrug concentrations and clinical presen-tation (50). CYP2C19 variants can also impact AEDmetabolism, with a substantial effect on pheno-barbital and to a lesser extent on phenytoin. Initialstudies also suggest that CYP2C19 variantsmay de-crease the rate of zonisamide metabolism (49).UDP glucuronosyltransferase (UGT) enzymes

catalyze the glucuronidation of xenobiotics as partof phase II drug metabolism. Polymorphisms ofUGT2B7 significantly decrease serum valproic acidlevels in epilepsy patients (51). UGT1A4 is the mainenzyme responsible for the glucuronidation oflamotrigine. The UGT1A4 L48V variant decreasesserum lamotrigine concentrations and affects itsoverall efficacy in both pediatric and adult patients(49, 51). Overall, the translation of genotypes ofrelevant genes to dose adjustments for individualpatients remains challenging, partly due to lack ofconclusive evidence as well as clear guidelines.

CONCLUSIONS

Due to their range of neurotransmission-modulating mechanisms, AEDs have been


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successfully used not only for the treatment of ep-ilepsy but also for various psychiatric conditionsand certain types of pain. AED therapy, either asmono- or polytherapy, successfully prevents sei-zures in approximately 70% of epilepsy patients.Identifying an effective AED for an individual pa-tient involves empirical testing of different drugs,often guided by TDM. Multiple assay modalities

are available for determining serum concentra-tions of AEDs. Furthermore, pharmacogeneticstesting can be applied during consideration ofAED therapy or when investigating unexpectedclearance kinetics. Overall, AEDs are an impor-tant drug type that must be carefully prescribedand monitored to achieve successful treatmentin a variety of conditions.

Author Contributions: All authors confirmed they have contributed to the intellectual content of this paper and havemet the following4 requirements: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b)drafting or revising the article for intellectual content; (c) final approval of the published article; and (d) agreement to be accountable forall aspects of the article thus ensuring that questions related to the accuracy or integrity of any part of the article are appropriatelyinvestigated and resolved.

Authors’ Disclosures or Potential Conflicts of Interest: No authors declared any potential conflicts of interest.

Role of Sponsor: No sponsor was declared.

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Additional Content on this Topic

Antiepileptic Drugs: Therapeutic Drug Monitoring of the Newer Generation DrugsMatthew D. Krasowski, CLN, June 2013.


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