8

Therapeutic Drug Monitoring

of Antiepileptic Medications
Matthew D. Krasowski
University of Iowa Hospitals and Clinics,
United States
1. Introduction
Medications used to treat and prevent seizures (antiepileptic medications, AEMs) have been
commonly managed by therapeutic drug monitoring (TDM) to optimize efficacy and avoid
toxicity (Neels et al., 2004; Patsalos et al., 2008). TDM has been applied mostly to the first-
generation AEMs that have been used clinically in the United States and Europe for several
decades, namely carbamazepine, ethosuximide, phenobarbital, phenytoin, primidone, and
valproic acid. First-generation AEMs generally have significant inter-individual variability
in their pharmacokinetics (absorption, distribution, metabolism, and excretion) and low
therapeutic indices. Two randomized, controlled studies of AEM TDM showed that
practitioners often apply information from TDM incorrectly (Frscher et al., 1981; Januzzi et
al., 2000). Consequently, improved education of medical practitioners on TDM is important
for the future.
In the last twenty-five years, 14 new AEMs have entered the market in the United States
and/or Europe (LaRoche & Helmers, 2004a,b; Patsalos, 1999). These drugs are sometimes
characterized as second- or third-generation AEMs and include the following drugs:
eslicarbazepine acetate, felbamate, gabapentin, lacosamide, lamotrigine, levetiracetam,
oxcarbazepine, pregabalin, rufinamide, stiripentol, tiagabine, topiramate, vigabatrin and
zonisamide. Eslicarbazepine acetate, lacosamide, rufinamide, and stiripentol have not yet been
approved in the United States. In contrast to the first-generation AEMs, the newer agents
generally (although not always) have wider therapeutic ranges and less adverse effects. This
chapter focuses on TDM of AEMs in treatment of epilepsy, emphasizing whether the
pharmacokinetics and clinical profile of the drug make TDM useful. AEMs are sometimes
used to treat disorders other than epilepsy such as trigeminal neuralgia, fibromyalgia, and
migraine headaches (Johannessen Landmark, 2008; LaRoche & Helmers, 2004a).
There are several main challenges in TDM of AEMs (Patsalos et al., 2008). First, there are no
simple diagnostic or laboratory tests for seizure disorders. The electroencephalogram (EEG)
is useful for diagnosis of seizure disorders but is too labor-intensive for long-term patient
observation. Second, seizures often occur unpredictably, sometimes with long periods of
time between episodes. Lastly, the toxicity of AEMs can resemble neurologic disease,
sometimes leading to inappropriate escalations of medication therapy even when the dose is
actually too high.
One of the most basic assumptions of TDM is that the concentration of drug being measured
correlates with the concentration at the target site of action (e.g., brain tissue). TDM of AEMs
www.intechopen.com

Novel Treatment of Epilepsy

134
is usually performed on plasma or serum, or occasionally on some other body fluid such as
saliva. TDM is difficult to apply when there are factors (e.g., irreversibility of action, drug
tolerance) that lessen the correlation between clinical effect and serum/plasma
concentration. AEMs with active metabolites also present a special challenge for TDM. For
drugs with active metabolites (e.g., oxcarbazepine, primidone), TDM can include
measurement of the concentrations of both parent drug and its metabolite(s) or just of the
metabolite(s).
TDM of AEMs in saliva has not yet been widely applied (Liu & Delgado, 1999), but has been
studied for ten drugs: carbamazepine (Ruiz et al., 2010; Tennison et al., 2004), gabapentin
(Benetello et al., 1997; Berry et al., 2003), lamotrigine (Incecayir et al., 2007; Malone et al.,
2006; Ryan et al., 2003), levetiracetam (Grim et al., 2003; Guo et al., 2007; Mecarelli et al.,
2007), oxcarbazepine (Cardot et al., 1995), phenobarbital (Tennison et al., 2004), phenytoin
(Tennison et al., 2004), topiramate (Miles et al., 2003), valproic acid (al Za'abi et al., 2003),
and zonisamide (Kumagai et al., 1993). Of these ten drugs, gabapentin and valproic acid are
clearly unsuited for salivary concentration analysis. Gabapentin shows low concentration in
saliva versus plasma (salivary concentrations are only ~5-10% that of serum or plasma) and
valproic acid has poor correlation between serum and salivary concentrations. Monitoring
of salivary concentrations of AEMs has clear appeal in some patient populations, especially
in the pediatric and geriatric populations. One study showed that salivary samples can be
collected by the patient and mailed to a clinical laboratory without loss of sample integrity
(Jones et al., 2005).
2. Application of TDM to AEMs
The most common reason to employ TDM for AEM therapy is that the drug shows
unpredictable and/or variable pharmacokinetics, often related to differences in drug
metabolism (Bialer, 2005; Perucca, 2006). Variability in pharmacokinetics may also occur due
to alterations in drug absorption or distribution. Metabolism of AEMs may vary due to
impaired organ function (typically kidney or liver), genetic factors, or drug-drug interactions.
Many of the AEMs are metabolized by hepatic enzymes including cytochrome P450 (CYP)
enzymes such as CYP3A4 and CYP2C9. A number of drugs are known to increase (induce)
the expression of hepatic drug-metabolizing enzymes. Well-known inducers include
carbamazepine, phenobarbital, phenytoin, rifampin (tuberculosis drug) and St. Johns wort
(herbal antidepressant) (Komoroski et al., 2004; Skolnick et al., 1976; Van Buren et al., 1984). In
patients taking AEMs, the co-ingestion of liver enzyme inducers can lead to inappropriately
low serum/plasma concentrations of the AEM if dose adjustments are not made. Some drugs
may inhibit metabolism of AEMs, often by acting as antagonists of CYP enzyme activity,
potentially leading to excessively high concentrations of drug unless the dose is reduced
appropriately. Valproic acid inhibits multiple liver enzymes and has been well-documented to
cause drug-drug interactions with other AEMs, which often requires careful TDM when
valproic acid is used in multi-drug regimens to treat epilepsy (Neels et al., 2004). AEMs may
be used in patients with some degree of renal impairment which can affect AEM
pharmacokinetics by decreased clearance, or by removal of drug during dialysis procedures.
In general, AEMs with low degrees of plasma protein binding are cleared more effectively by
dialysis than AEMs that are highly protein bound (Lacerda et al., 2006).
Special considerations apply to TDM of AEMs that are highly (> 90%) bound to serum
proteins. For these AEMs, monitoring of unbound (free) concentrations may be clinically
www.intechopen.com

Therapeutic Drug Monitoring of Antiepileptic Medications

135
useful (Dasgupta, 2007). Serum protein concentrations of drug can vary due to factors
such as drug interactions, liver disease, pregnancy and old age. Co-administered
medications (e.g., valproic acid) or endogenous substances can displace drugs from serum
protein binding sites, increasing free drug concentrations. Uremia, typically secondary to
renal failure, can also displace AEMs from serum protein binding sites. Free drug
concentrations can be measured by preparing an ultrafiltrate of plasma (e.g., by
centrifugation through a membrane) and then analyzing the concentration of drug. The
main technical challenge is that free drug concentrations may be substantially lower than
total drug concentrations in drugs that are highly bound to plasma proteins. Therefore,
analytical methods to measure free drug concentrations need to have lower limits of
quantitation than methods to measure total drug concentrations. Analytical methods used
to measure total drug concentrations may have insufficient analytical sensitivity for free
drug analysis (Dasgupta, 2007). A further practical challenge is that the ultrafiltration
process needed for free drug analysis is not easily automated and adds processing time
and effort to the clinical laboratory analysis.
The last common reason for TDM of AEMs is to assess compliance (adherence) to therapy
such as in a patient who shows a lack of clinical response or the loss of efficacy in a therapy
that was previously effective (Patsalos et al., 2008). Epilepsy therapy can occur over long
periods of time even in the absence of seizures. Similar to other medications that may be
taken chronically (e.g., anti-depressants, anti-hypertensives), patients may skip doses or
stop taking the medication due to side effects, medication expense, or other factors.
3. Reference ranges for AEMs
Reference ranges for AEMs are challenging to establish. Ideally, TDM would guide
physicians towards serum/plasma concentrations that optimally control seizures while
avoiding or minimizing adverse effects. The reference range of an AEM can be defined by
a lower limit below which therapeutic effect is unlikely and an upper limit above which
toxicity is likely (Patsalos et al., 2008). Reference ranges may vary with different types of
seizures, or when AEMs are used for other purposes such as treatment of bipolar disorder
or chronic pain. A special challenge occurs with defining reference ranges for the newer
generation AEMs, which were generally studied in clinical trials as adjunctive therapy and
not as monotherapy. Perucca has advocated the concept of individual therapeutic
concentrations (Perucca, 2000) wherein a patient is treated until good seizure control is
achieved. The serum/plasma concentration at which good seizure control occurs serves as
the patients individual therapeutic concentration that can be used as the target
concentration to maintain during chronic therapy. TDM for AEMs is especially important
when there are factors that can alter AEM pharmacokinetics, e.g., pregnancy, impaired
kidney or liver function, or concomitant therapy with hepatic enzyme-inducing or
inhibiting drugs.
With the background and theory on TDM above, each of the AEMs will be discussed in
turn with regard to TDM. Table 1 summarizes the pharmacokinetic properties of the
AEMs, while Table 2 presents a summary of the justifications of TDM for the AEMs.
References for reference ranges used in Table 1 are as follows: carbamazepine,
clonazepam, phenobarbital, phenytoin, primodone, valproic acid (Hardman et al., 1996),
felbamate (Faught et al., 1993; Sachdeo et al., 1992), gabapentin (Lindberger et al., 2003),
lacosamide (Kellinghaus, 2009), lamotrigine (Bartoli et al., 1997), levetiracetam (Leppik et
www.intechopen.com

Novel Treatment of Epilepsy

136
al., 2002), oxcarbazepine (10-hydroxycarbazepine metabolite) (Friis et al., 1993),
pregabalin (Patsalos et al., 2008), stiripentol (Farwell et al., 1993), tiagabine (Uthman et al.,
1998), topiramate (Johannessen et al., 2003), vigabatrin (Patsalos, 1999), and zonisamide
(Glauser & Pippenger, 2000; Mimaki, 1998).
4. TDM of the first generation AEMs
The first generation AEMs are commonly managed by TDM, in large part due to complex
and variable pharmacokinetics. In general, the first generation agents have narrow
therapeutic indices, with high plasma concentrations frequently associated with central
nervous system (CNS) and other adverse effects. Several of the first generation AEMs,
especially phenytoin, have high degrees of binding to plasma proteins; consequently, free
drug concentrations in plasma can be clinically useful in some patients (Dasgupta, 2007).
Three of the first generation AEMs (carbamazepine, phenobarbital, and phenytoin) are
strong inducers of liver drug-metabolizing enzymes, particularly of CYP3A4. CYP3A4 has
very wide substrate specificity including for cyclosporine, tacrolimus, and theophylline, as
well as endogenous compounds such as estradiol and vitamin D (Luo et al., 2004). The
accelerated metabolism of ethinyl estradiol that can occur during therapy with CYP3A4
inducers can lead to ineffectiveness of estrogen-containing oral contraceptives and
unintended pregnancy (Crawford, 2002). Chronic therapy with carbamazepine,
phenobarbital, and phenytoin is also well-known to have the potential risk of osteomalacia
secondary to vitamin D deficiency (Zhou et al., 2006).
4.1 Carbamazepine
Carbamazepine has complicated pharmacokinetics that favors use of TDM (Neels et al.,
2004; Warner et al., 1998). Carbamazepine is generally well-absorbed following oral
administration; however, absorption may be delayed considerably by large doses. The
metabolism of carbamazepine is quite complex, with the main metabolite being
carbmazepine 10,11-epoxide, a compound that shows similar anticonvulsant activity to
carbamazepine. In chronic therapy, concentrations of the epoxide metabolite may reach
plasma concentrations 50% that of the parent drug. As described above, carbamazepine is a
strong inducer of liver drug-metabolizing enzymes, including the CYP3A4 enzyme that
metabolizes carbamazepine itself. Thus, carbamazepine represents an example of a drug
that shows autoinduction, namely that the metabolism of carbamazepine increases as the
drug is used chronically (Pitlick & Levy, 1977). Auto-induction is usually complete by 2-3
weeks, although it can take longer in some individuals.
Like other first generation AEMs, neurological side effects are common with high doses of
carbamazepine, particularly when the plasma concentration exceeds 9 mg/L.
Carbamazepine can also produce rare idiosyncratic adverse effects including severe
dermatologic reactions such as Steven-Johnson Syndrome or toxic epidermal necrolysis.
There is an association with severe skin reactions during carbamazepine therapy with the
human leukocyte antigen (HLA) allele HLA-B*1502 which is common in patients with South
Asian ancestry, particularly India (Alfirevic et al., 2006; Lonjou et al., 2006).
Pharmacogenetic testing for this allele may be useful in patients of South Asian descent who
are being considered for therapy with carbamazepine.
www.intechopen.com

Therapeutic Drug Monitoring of Antiepileptic Medications

137
Drug
Oral
bioavailability
Serum
protein
binding
Time to
peak conc.
(hrs)
Serum half-
life (hrs)
Reference
range in serum
(mg/L)
Carbamazepine >70 75 4-8 10-20 4-10
Clonazepam >95 85 1-2 20-26 0.005-0.07
Eslicarbazepine
acetate
80 30 1-4 20-24 Not established
Ethosuximide >90 0 2-4 30-50 40-100
Felbamate >90 25 2-6 16-22
a
30-60
Gabapentin <60 0 2-3 5-9 2-20
Lacosamide 95 15 0.5-4 12-13 5-10
Lamotrigine 95 55 1-3 15-35
a, b
3-14
Levetiracetam 95 0 1 6-8 12-46
Oxcarbazepine 90 40 3-6 8-15
a
3-35
Phenobarbital >95 50 4-12 90-110 10-25
Phenytoin 90 >95 4-12 6-24 10-20
Primidone >90 20 2-4 10-20 8-12
Pregabalin 90 0 1-2 5-7 2.8-8.3
Rufinamide 85 30 5-6 8-12
a
Not established
Stiripentol 90 99 1-2 Variable 4-22
Tiagabine 90 96 1-2 5-9
a
0.02-0.2
Topiramate 80 15 2-4 20-30 5-20
Valproic acid >95 >90 1-4 11-17 30-100
Vigabatrin 60 0 1-2 5-8 0.8-36
Zonisamide 65 50 2-5 50-70
a
10-40
a
Serum half-life significant decreased with concomitant therapy with liver enzyme inducers (rifampin,
carbamazepine, phenobarbital, phenytoin, St. Johns wort)
b
Serum half-life significantly increased with concomitant therapy with valproic acid.
Table 1. Pharmacokinetic Parameters and Reference Ranges for the AEMs
TDM is frequently used in carbamazepine therapy due to the challenging pharmacokinetics.
Monitoring of carbamazepine is usually achieved by a variety of marketed immunoassays
that have high specificity for the parent drug and limited cross-reactivity with the
metabolites (Warner et al., 1998). TDM sometimes also includes monitoring of the epoxide
metabolite, which can contribute a substantial amount of the therapeutic effect. One
challenge of monitoring the epoxide metabolite is that commercial immunoassays specific
for this metabolite are not available, and thus a technology such as high-performance liquid
chromatography (HPLC) is generally needed, which usually means the analysis is
performed at reference laboratories.
4.2 Clonazepam
Clonazepam is a benzodiazepine used in treatment of epilepsy, as well as in a variety of
other conditions such as anxiety or panic disorders, restless legs syndrome, and mania (Riss
et al., 2008). Other benzodiazepines such as diazepam and lorazepam are used commonly
for acute management of seizures but not as often for long-term management. In general,
www.intechopen.com

Novel Treatment of Epilepsy

138
benzodiazepines are limited by tolerance during chronic therapy. Clonazepam is extensively
metabolized, with less than 1% of the administered dose recovered as parent drug. The main
metabolite is 7-aminoclonazepam, which is therapeutically inactive.
TDM has a relatively limited role in clonazepam therapy (Warner et al., 1998). Plasma
concentrations do not correlate all that tightly with therapeutic effect, with a wide range of
concentations (5 to 70 ng/mL) associated with effective management of seizures. Higher
plasma concentrations are associated with increased frequency of CNS side effects such as
drowsiness or lethargy. Other than to establish an individual therapeutic concentration or
to assess compliance with therapy or evaluate possible toxic effects, monitoring of
clonazepam is generally of limited value.
4.3 Ethosuximide
Ethosuximide has excellent bioavailability and is not bound to any appreciable degree to
plasma proteins (Brodie & Dichter, 1997; Perucca, 1996). Approximately 25% of the ingested
drug is excreted unchanged. The remainder of the excretion is mostly to a hydroxyethyl
metabolite, which is inactive with respect to anticonvulsant effect. Ethosuximide has a fairly
wide therapeutic range with effective antiseizure activity commonly occurring with plasma
concentrations of 40-100 mg/L. CNS and gastrointestinal side effects are more common with
plasma concentrations exceeding 100 mg/L. TDM is commonly applied to ethosuximide
therapy, although not as commonly as first generation AEMs such as carbamazepine,
phenobarbital, and phenytoin that have more challenging pharmacokinetics (Warner et al.,
1998).
4.4 Phenobarbital and primidone
Phenobarbital and primidone are structurally related compounds used in the management
of epilepsy (Brodie & Dichter, 1997; Perucca, 1996). Primidone is converted to phenobarbital
and phenylethylmalonamide (PEMA) by metabolism, with both metabolites contributing
significant anticonvulsant activity. Phenobarbital and primidone show excellent absorption
following oral dosing, although absorption of phenobarbital can be slow, especially with
high doses. One of the striking pharmacokinetic features of phenobarbital is a long half-life,
up to 100 hrs or more in adults and somewhat shorter (~80 hrs) in neonates.
TDM is commonly use for both phenobarbital and primidone (Warner et al., 1998). Plasma
concentrations of 10-35 mg/L are generally recommended for phenobarbital management of
seizures. Above 35 mg/L, CNS-related adverse effects are more frequent. TDM of
primidone is complicated to interpret due to the formation of two active metabolites
(phenobarbital and PEMA). Monitoring of primidone therapy often involves measurement
of both primidone and phenobarbital plasma concentrations, both of which can be done
with commercial immunoassays.
4.5 Phenytoin
Phenytoin is likely the AEM for which TDM is applied most frequently (Warner et al., 1998).
Phenytoin has very challenging pharmacokinetic properties. While absorption of the drug
following ingestion is high, time to peak concentrations are variable (3-12 hrs) depending on
dosage and intake relative to meals. Phenytoin is extensively bound to plasma proteins, and
clinically significant increased free fractions are observed in neonates, patients with
www.intechopen.com

Therapeutic Drug Monitoring of Antiepileptic Medications

139
hypoalbuminemia, and in patients with uremia due to renal failure (Dasgupta, 2007).
Phenytoin has complex metabolism, with saturation of hepatic enzymes at therapeutic
plasma concentrations, leading to zero-order (saturation) elimination kinetics. Two of the
enzymes that catalyze the metabolism of phenytoin, CYP2C9 and CYP2C19, show
pharmacogenetic variation, with individuals with lower catalytic acvitity (poor
metabolizers) at risk for developing supra-therapeutic concentrations (Ninomiya et al.,
2000). Phenytoins unusual pharmacokinetic profile makes maintaining patients at
therapeutic plasma concentrations a tricky and time-consuming goal that depends on
recurrent TDM. Unfortunately, TDM cannot currently predict some of the annoying and
occasionally serious adverse effects of phenytoin such as dermatologic reactions, hirsutism,
and gingival overgrowth (Perucca, 1996). The latter two reactions occur unpredictably with
chronic phenytoin therapy.
4.6 Valproic acid
Valproic acid has overall excellent bioavailability, although absorption can be delayed
considerably with higher doses or when the drug is ingested with meals (Brodie & Dichter,
1997; Perucca, 1996). Valproic acid is approximately 90% bound to plasma proteins.
Although measurement of free valproic acid concentrations in plasma is usually not needed
for TDM, patients with hypoalbuminemia are at higher risk of having supra-therapeutic free
concentrations. Valproic acid is extensively metabolized, with some of the metabolites
having some anticonvulsant activity. Valproic acid is an inhibitor of multiple CYP enzymes
and as such can cause drug-drug interactions, including with other AEMs such as
carbamazepine, felbamate, lamotrigine, phenobarbital, phenytoin, and stiripentol (Besag &
Berry, 2006). Valproic acid can cause hepatitis (with elevations of enzymes such as alanine
aminotransferase), in some cases manifesting as fulminant liver failure. Consequently,
many physicians periodically monitor hepatic enzymes and also instruct patients to seek
medical attention with any signs or symptoms of liver damage such as abdominal pain or
jaundice.
Valproic acid has a therapeutic range of 30-100 mg/L. CNS side effects are more common
when plasma concentrations exceed 100 mg/L although some patients may have plasma
concentrations of 150 mg/L or higher without adverse effects. Given the wide range of
plasma concentrations associated with successful therapy, TDM can be especially valuable
in valproic acid therapy in establishing an individual therapeutic concentration (Warner et
al., 1998).
5. TDM of the new generation AEMs
5.1 Eslicarbazepine
Eslicarbazepine acetate [(S)-licarbazepine acetate] is a pro-drug that is rapidly and nearly
completely metabolized to eslicarbazepine by liver esterases (Falcao et al., 2007; Maia et al.,
2005). TDM focuses on eslicarbazepine and not on the minor metabolites oxcarbazepine
(also used as an AEM) and (R)-licarbazepine. Unlike carbamazepine, eslicarbazepine does
not exhibit auto-induction in metabolism, has low (~30%) binding to serum proteins, and
overall has a low potential for drug-drug interactions (Almeida et al., 2010; Bialer et al.,
2009). Eslicarbazepine has an elimination half-life of 20-24 hr during chronic administration
www.intechopen.com

Novel Treatment of Epilepsy

140
(Almeida et al., 2005). Mild to moderation hepatic failure has minimal impact on the
pharmacokinetics of eslicarbazepine (Almeida et al., 2008). The main route of elimination of
eslicarbazepine and other minor metabolites of eslicarbazepine acetate is via the kidneys,
with moderate or severe renal failure significantly reducing the clearance of eslicarbazepine.
Hemodialysis effectively removes eslicarbazepine and other metabolites of eslicarbazepine
acetate (Maia et al., 2008).
Overall, TDM has a minor role in the therapeutic use of eslicarbazepine given the relatively
predictable pharmacokinetics of the drug. TDM for eslicarbazepine may be useful in
patients with renal failure. An enantioselective high-performance liquid chromatography-
ultraviolet (HPLC-UV) method has been developed for the specific monitoring of
eslicarbazepine and its metabolites (Alves et al., 2007).
5.2 Felbamate
Felbamate is approved in the United States for the treatment of partial seizures in adults and
for Lennox-Gastaut Syndrome, a type of childhood epilepsy that is often refractory to AEM
therapy (Bourgeois, 1997; Pellock et al., 2006). The use of felbamate has been limited due to
the risks of aplastic anemia and severe liver failure, which led to revised labeling and
restricted use of felbamate (Pellock et al., 2006). It is suspected that one or more metabolites
of felbamate mediate the rare but serious adverse effects (Shumaker et al., 1990).
Approximately 50% of the parent drug is metabolized by the liver to inactive metabolites
(Shumaker et al., 1990; Thompson et al., 1999). Inducers of hepatic metabolism increase the
metabolism of felbamate (Sachdeo et al., 1993; Wagner et al., 1991), while valproic acid
inhibits the metabolism (Ward et al., 1991).
A clear reference range has not been established for felbamate, but seizure control usually
occurs with serum/plasma concentrations of 30-60 mg/L (Faught et al., 1993; Sachdeo et al.,
1992). Children clear felbamate approximately 20-65% faster than adults (Perucca, 2006).
TDM may be helpful in felbamate therapy given the variable metabolism across individuals.
Close monitoring of liver function and blood counts are advised during felbamate therapy,
with the goal to discontinue therapy if any signs of bone marrow or liver damage appear.
5.3 Gabapentin
Gabapentin was originally approved in the United States for the treatment in epilepsy but is
currently used more often for the management of chronic pain (LaRoche & Helmers, 2004b;
McLean, 1995). Gabapentin is rapidly absorbed by the L-amino acid transport system
(Vollmer et al., 1988), and a study published in 1998 showed possible saturability of this
system, with a decrease in bioavailability at doses of 4,800 mg/day of gabapentin as
compared to lower doses (Gidal et al., 1998). However, a later study showed linear
absorption up to 4,800 mg/day (Berry et al., 2003). Gabapentin does not distribute much
into saliva, precluding the utility of salivary gabapentin concentrations for TDM (Berry et
al., 2003). Gabapentin is not metabolized to any appreciable degree and has low binding to
serum proteins (Vollmer et al., 1988). The bulk of excretion is via the kidneys, with the half-
life increasing in patients with renal failure. Hemodialysis effectively clears gabapentin
(Hung et al., 2008; Wong et al., 1995).
Gabapentin does not have a clear reference range (Armijo et al., 2004), although effective
control of seizures generally requires concentrations of 2 mg/L or higher (Sivenius et al.,
www.intechopen.com

Therapeutic Drug Monitoring of Antiepileptic Medications

141
1991). An approximate reference range of 2-20 mg/L for management of seizure disorders
has been proposed (Lindberger et al., 2003). TDM is not usually necessary for gabapentin
therapy other than to adjust dosing in patients with impaired kidney function or to assess
adherance to therapy (Patsalos et al., 2008)
5.4 Lacosamide
Lacosamide is a novel functionalized amino acid that enhances inactivation of voltage-
gated sodium channels (Curia et al., 2009; Perucca et al., 2008b). Lacosamide was
approved in Europe in 2008 for partial-onset seizures in patients 16 years and older
(Chung et al., 2010). Lacosamide has high bioavailability (~100%) and serum protein
binding (Ben-Menachem et al., 2007; Luszczki, 2009). Approximately 60% of the parent
drug is metabolized, mainly by CYP2C19 to an inactive metabolite. The remaining 40% is
excreted unchanged by the kidneys. The low plasma protein binding of lacosamide
suggests that the drug should be cleared effectively by dialysis, although data on this has
not yet been published (Lacerda et al., 2006). The half-life of lacosamide is approximately
12 hours. Drug-drug interactions involving lacosamide appear to be uncommon (Beydoun
et al., 2009; Johannessen Landmark & Patsalos, 2010). The predictable pharmacokinetics of
lacosamide, along with lack of clinically significant drug-drug interactions, suggests a
limited role for TDM in managing lacosamide pharmacotherapy. Consequently, TDM of
lacosamide has limited benefit except in patients with severe liver and/or kidney failure,
or to assess compliance with therapy (Cross & Curran, 2009; Thomas et al., 2006).
5.5 Lamotrigine
Lamotrigine has been approved by the United States Food and Drug Administration (FDA)
for treatment of partial seizures and bipolar disorder (Neels et al., 2004; Patsalos et al., 2008).
The major adverse effect of lamotrigine is dermatologic reaction, including severe Stevens-
Johnson and toxic epidermal necrolysis syndromes (Knowles et al., 1999). Harm from skin
reactions have been reduced by the clinical practice of cautiously escalating dose and
promptly ceasing therapy if potential skin reactions appear. One of the major advantages of
lamotrigine is a solid safety record in pregnancy, which contrasts with the teratogenic effects
of first-generation AEMs such as carbamazepine, phenytoin, and valproic acid (Sabers &
Tomson, 2009; Tomson & Battino, 2007).
Lamotrigine is quickly and completely absorbed from the gastrointestinal tract and is only
~50% bound to serum proteins. Lamotrigine distributes into saliva, and salivary lamotrigine
concentrations correlate well with those in serum, allowing for saliva to serve as an
alternative sample for TDM (Ryan et al., 2003; Tsiropoulos et al., 2000). Lamotrigine is
extensively metabolized, principally by glucuronidation to form an inactive metabolite
(Hussein & Posner, 1997; Rambeck & Wolf, 1993). Similar to carbamazepine, lamotrigine
shows the phenomenon of autoinduction during chronic therapy. Autoinduction is usually
complete within two weeks, with a ~20% reduction in steady-state serum/plasma
concentrations if the dose is not increased (Hussein & Posner, 1997). Classic liver enzyme
inducers significantly increase the metabolism of lamotrigine, reducing the serum half-life
from 15-35 hr to approximatley 8-20 hr (Hussein & Posner, 1997; Rambeck & Wolf, 1993).
Ethinyl estradiol-containing oral contraceptives also significantly increase the clearance of
lamotrigine (Reimers et al., 2007; Sabers et al., 2001; Sabers et al., 2003). Valproic acid inhibits
the metabolism of lamotrigine and can increase the serum half-life to up to 60 hr (Biton,
www.intechopen.com

Novel Treatment of Epilepsy

142
2006; Ramsay et al., 1991). Severe renal failure increases the serum half-life to ~50 hr in
patients. Hemodialysis effectively clears lamotrigine (Fillastre et al., 1993). The clearance of
lamotrigine is higher in children (Bartoli et al., 1997; Perucca, 2006) and much higher
(~300%) in pregnancy (Perucca, 2006). A reference range of 3-14 mg/L has been advocated
for refractory epilepsy therapy (Morris et al., 1998). The risk of toxicity increases
significantly when serum/plasma concentrations exceed 15 mg/L (Besag et al., 1998; Morris
et al., 1998).
TDM of lamotrigine is useful for several main reasons. First, the drug shows significant
interindividual variation in liver metabolism, which can be affected by concomitant
medications. Second, the clearance of lamotrigine varies across development and
particularly increases during pregnancy (Pennell et al., 2008). Lastly, there is a fairly clear
concentration (> 15 mg/L) above which adverse effects become more frequent (Bartoli et al.,
1997; Biton, 2006; Rambeck & Wolf, 1993).
5.6 Levetiracetam
Levetiracetam is a novel anticonvulsant structurally unrelated to other AEMs (Klitgaard,
2001; Leppik, 2001). Following oral administration, levetiracetam is rapidly and nearly
completely absorbed, with the rate of oral absorption slowed by co-ingestion with food (Fay
et al., 2005; Patsalos, 2000). Levetiracetam distribute extensively into saliva, with salivary
concentrations usually being slightly higher than serum concentrations in patients receiving
chronic therapy (Lins et al., 2007). Salivary and serum levetiracetam concentrations correlate
well with one another, making saliva an alternative sample to perform TDM (Grim et al.,
2003; Mecarelli et al., 2007).
Levetiracetam shows low binding to serum proteins and has linear pharmacokinetics.
Nearly 100% of the absorbed drug is ultimately excreted by the kidneys (Patsalos, 2004),
with approximately two-thirds as the parent drug and one-thirds as a metabolite that is
formed by hydrolysis in the blood (Patsalos et al., 2006). There is very little, if any,
metabolism of levetiracetam by the liver and, consequently low probability of significant
drug-drug interactions (Johannessen Landmark and Patsalos, 2010). Given the low plasma
protein binding, levetiracetam is likely efficiently cleared by hemodialysis (Lacerda et al.,
2006). The serum half-life of levetiracetam is shorter in adult (6-8 hr) compared to neonates
(16-18 hr) (Patsalos et al., 2008). Clearance of levetiracetam increases significantly in
pregnancy, with an approximately 60% decrease in serum concentrations (Tomson and
Battino, 2007).
A reference range of 12-46 mg/L has been proposed based on a study of 470 patients in a
specialty epilepsy clinic (Leppik et al., 2002). Other than to assess compliance or investigate
potential toxicity, the main value of TDM for levetiracetam is in adjusting dosage for renal
insufficiency (Patsalos, 2000, 2004; Patsalos et al., 2008; Radtke, 2001). In collecting samples
for drug monitoring, serum or plasma should be separated from whole blood rapidly, as in
vitro hydrolysis of levetiracetam can occur in the blood tube and thus lead to artifactually
low concentrations (Patsalos et al., 2006).
5.7 Oxcarbazepine
Oxcarbazepine has a chemical structure related to carbamazepine but causes less
induction of liver enzymes. Oxcarbazepine is rapidly and completely absorbed and
www.intechopen.com

Therapeutic Drug Monitoring of Antiepileptic Medications

143
metabolized to its monohydroxy derivative 10-hydroxycarbazepine (Larkin et al., 1991;
Lloyd et al., 1994; May et al., 2003). 10-Hydroxycarbazepine is further metabolized,
primarily by glucuronidation. The clearance of 10-hydroxycarbazepine is reduced in
renal insufficiency (Rouan et al., 1994) and in the elderly (Perucca, 2006). The clearance of
10-hydroxycarbazepine is increased in pregnancy (Christensen et al., 2006; Mazzucchelli
et al., 2006) and in patients taking liver enzyme-inducing drugs (May et al., 2003).
Children require higher doses of oxcarbazepine per body weight than adults (Battino et
al., 1995). 10-Hydroxycarbazepine and oxcarbazepine have similar potencies for
anticonvulsant activity; however, 10-hydroxycarbazepine generally accumulates to higher
concentrations in serum and thus accounts for the majority of the antiseizure activity
(Lloyd et al., 1994).
Consequently, TDM for oxcarbazepine generally focuses on measurement of serum/plasma
concentrations of the monohydroxy metabolite (Patsalos et al., 2008). Although 10-
hydroxycarbazepine distributes into saliva, there are dose-dependent variations in the
correlation between 10-hydroxycarbazepine saliva and serum concentrations that limit the
utility of saliva as an alternative specimen for TDM of oxcarbazepine (Cardot et al., 1995;
Kristensen et al., 1983; Miles et al., 2004). In clinical research studies, a wide range of 10-
hydroxycarbazepine serum concentrations (3-35 mg/L) were observed to be clinically
effective in seizure treatment (Friis et al., 1993), with toxic side effects being more common
at serum/plasma concentrations of 35 mg/L or higher (Striano et al., 2006). TDM for
oxcarbazepine is justified when changes are expected that might alter 10-
hydroxycarbazepine clearance including pregnancy, concomitant use of liver enzyme-
inducing drugs, or renal insufficiency.
5.8 Pregabalin
Pregabalin was originally designed to be a more potent analog of gabapentin (Selak, 2001)
and shares many clinical similarities to gabapentin, including widespread use to manage
conditions other than epilepsy such as neuropathic pain and fibromyalgia (Acharya et al.,
2005; LaRoche & Helmers, 2004a). Pregabalin has very advantageous pharmacokinetics
including high bioavailability, low binding to plasma proteins, minimal metabolism, and no
significant drug-drug interactions (Busch et al., 1998). The majority of the absorbed dose
(~98%) is excreted unchanged in the urine. Clearance of pregabalin approximates
glomerular filtration rate (Corrigan et al., 2001), and dosing of pregabalin may need
adjustment in patients with impaired renal function (Randinitis et al., 2003). Pregabalin is
effectively cleared by hemodialysis (Yoo et al., 2009). An approximate reference range of
2.8-8.3 mg/L has been proposed for the use of pregabalin in managing seizures (Patsalos et
al., 2008). The favorable pharmacokinetics of pregabalin generally obviates the need for
TDM, other than to adjust dosing during renal failure or to assess compliance. If monitoring
is performed, the short half-life of pregabalin (4.6-5.8 hr) (Bockbrader et al., 2000)
necessitates that care must be taken in the timing of blood draws for TDM.
5.9 Rufinamide
Rufinamide is a novel anticonvulsant approved for use in Europe in January 2007 and in the
United States in December 2008 for Lennox-Gastaut syndrome (Hakimian et al., 2007;
Heaney & Walker, 2007; Wheless & Vazquez, 2010; Wisniewski, 2010). Rufinamide is well-
www.intechopen.com

Novel Treatment of Epilepsy

144
absorbed (80-90%) following oral administration (Perucca et al., 2008a). The peak exposure
to rufinamide may increase significantly when taken with food as compared to an empty
stomach. Consequently, patients are often counseled to take rufinamide in the same
temporal relation to meals. Rufinamide is extensively metabolized, primarily by
carboxyesterases, with only trace amounts of the parent drug excreted in feces or urine. The
primary metabolite is inactive and mainly excreted by the kidneys.
Hepatic enzyme inducers such as carbamazepine and rifampin increase the excretion of
rufinamide (Perucca et al., 2008a). Impaired renal function has minimal effect on clearance
of rufinamde; however, increased doses of rufinamide are often needed in patients receiving
hemodialysis due to removal of the drug by the dialysis procedure. Although reference
ranges for rufinamide have not been well-defined yet, serum/plasma concentrations
generally correlate with seizure control, allowing for determination of an individual
therapeutic concentration that can be monitored over the course of chronic therapy
(Luszczki, 2009; Perucca et al., 2008a; Wheless & Vazquez, 2010) TDM for rufinamide can be
especially helpful in patients receiving hemodialysis or who are also taking liver enzyme
inducers.
5.10 Stiripentol
Stiripentol is an AEM that was originally approved in Europe in 2001 but is currently
infrequently used. Stiripentol is rapidly absorbed following oral administration but has
overall low bioavailability, in large part due to extensive first-pass metabolism by the liver.
The hepatic metabolism of stiripentol is very complex, with at least 5 different metabolic
pathways generating over a dozen metabolites. The dosing of stiripentol is further
complicated by zero-order (saturation) elimination kinetics, with a marked decrease in
clearance with increased dosage (Levy et al., 1983). Stiripentol is also highly (>99%) protein
bound and prone to drug interactions that can alter the free fraction (Lacerda et al., 2006). A
well-defined reference range for stiripentol has not been established, although one study
showed that serum concentrations of 4-22 mg/L correlate with control of absence seizures in
children (Farwell et al., 1993).
The complex pharmacokinetics of stiripentol (extensive hepatic metabolism, high binding to
plasma protein, and saturation kinetics) resemble that of phenytoin (Luszczki, 2009).
Measurement of the free drug fraction of stiripentol may be clinically useful; however,
methods to measure free fractions have not yet been reported. When used in combination
AEM therapies, stiripentol may cause drug-drug interactions by inhibiting the metabolism
of carbamazepine, clobazam, phenobarbital, phenytoin, and valproic (Levy et al., 1984; Tran
et al., 1997; Tran et al., 1996).
5.11 Tiagabine
Tiagabine is currently approved in the United States and Europe but is used infrequently
due to a propensity to cause non-convulsive status epilepticus (Eckardt & Steinhoff, 1998;
Kellinghaus et al., 2002; Schapel & Chadwick, 1996). Tiagabine is rapidly absorbed with
high bioavailability but, unlike many of the other newer AEMs, is highly bound to
proteins (> 96%) (Gustavson & Mengel, 1995). Co-therapy with valproic acid can increase
the free concentrations of tiagabine by displacing tiagabine from serum protein binding
sites (Patsalos et al., 2002). The hepatic metabolism of tiagabine is complex and extensive
www.intechopen.com

Therapeutic Drug Monitoring of Antiepileptic Medications

145
with less than 1% of the absorbed parent drug excreted unchanged (Gustavson & Mengel,
1995). The metabolism of tiagabine can be altered by concomitant therapy with liver
enzyme inhibitors or inducers. The serum half-life is typically 5-9 hr for patients on
tiagabine monotherapy. The half-life is reduced to 2-4 hr in patients receiving enzyme
inducers (So et al., 1995). The serum half-life increases to 12-16 h in severe liver failure
(Lau et al., 1997). Children have higher clearance than adults (Gustavson et al., 1997).
Renal dysfunction does not significantly impact the pharmacokinetics of tiagabine (Cato
et al., 1998).
The inter-individual variation in hepatic metabolism makes tiagabine a candidate for
TDM. Further, the extensive binding of tiagabine to plasma proteins further suggests that
measurement of free drug concentrations may be clinically useful (Dasgupta, 2007).
However, a clear relationship between tiagabine serum/plasma concentration and
therapeutic efficacy has not yet been established, with a broad reference range of 20-200
ng/mL proposed (Patsalos et al., 2008; Uthman et al., 1998). For measurement of free drug
concentrations, analytical sensitivity is an issue, with some assays having insufficiently
low limits of sensitivity to measure clinically relevant free drug concentrations (Williams
et al., 2003). Consequently, such analysis is only performed at specialized reference
laboratories.
5.12 Topiramate
Topiramate has approval for treatment of epilepsy of children and adults, and also for the
treatment of migraine headaches (LaRoche & Helmers, 2004a). Topiramate has high
bioavailability (~80%) and low binding to serum proteins (Easterling et al., 1988). Salivary
topiramate concentrations correlate well with those in serum (with salivary concentrations
being roughly 0.9 that in serum), which makes saliva an alternative specimen type for TDM
(Jones et al., 2005; Miles et al., 2003). Approximately 50% of the absorbed dose is
metabolized by the liver. Hepatic enzyme inducers can decrease the serum half-life of
topiramate from 20-30 hr to approximately 12 hr (Britzi et al., 2005; Sachdeo et al., 1996).
Children generally eliminate topiramate faster than adults (Perucca, 2006; Rosenfeld et al.,
1999). A reference range of 5-20 mg/L has been proposed for topiramate for epilepsy
therapy (Johannessen et al., 2003). TDM of topiramate is most useful due to variability in
metabolism.
5.13 Vigabatrin
Vigabatrin is an irreversible inhibitor of GABA transaminase, an enzyme that catalyzes
the elimination of GABA (Rey et al., 1992; Schechter, 1989). Vigabatrin has high
bioavailability (60-80%), low binding to serum proteins and is primarily excreted
unchanged in the urine (Durham et al., 1993; Rey et al., 1992). Dose reductions of
vigabatrin are generally needed in patients with renal failure (Rey et al., 1992). Clearance
of vigabatrin increased during hemodialysis (Jacqz-Aigrain et al., 1997). The irreversible
action of vigabatrin on its molecular target is likely the reason a wide range of
serum/plasma concentrations (0.8-36 mg/L) of vigabatrin are associated with successful
treatment with with vigabatrin. Other than to assess compliance or possible drug
overdose, there is little value in monitoring vigabatrin plasma/serum concentrations
(Patsalos, 1999).
www.intechopen.com

Novel Treatment of Epilepsy

146
Drug
Need for
TDM
Factors Favoring TDM Limitations of TDM
Carbamazepine Frequent
Auto-induction of metabolism;
drug-drug interactions; high
serum protein binding
Free drug
concentrations needed
for some patients
Clonazepam Uncommon
Distinguish tolerance from
inadequate dosing
Wide reference range;
low toxicity incidence
Eslicarbazepine
acetate
Intermediate
Decreased clearance with chronic
dosing and liver failure
Generally predictable
pharmacokinetics
Ethosuximide Intermediate Complex metabolism
Wide reference range,
variable toxicity range
Felbamate Intermediate
Variable metabolism, potential
for severe toxicity
Uncertain reference
range
Gabapentin Uncommon
Decreased clearance with renal
failure
Wide reference range;
low toxicity incidence
Lacosamide Uncommon Predictable dosing
Lamotrigine Frequent
Variable metabolism; significant
drug-drug interactions

Levetiracetam Intermediate
Decreased clearance with renal
failure
Wide reference range,
low toxicity incidence
Oxcarbazepine
Intermediate
to Frequent
Variable metabolism, well-
defined toxic range

Phenobarbital Frequent
Drug-drug interactions, long half-
life
Tolerance to drug can
complicate TDM
Phenytoin Frequent
Variable absorption; high serum
protein binding; drug-drug
interactions; zero-order kinetics
Free drug
concentrations needed
in some populations
Primidone Intermediate
Long half-life of metabolites,
potential for toxicity
Need to monitor
phenobarbital as well
Pregabalin Uncommon
Decreased clearance with renal
failure
Wide reference range,
low toxicity incidence
Rufinamide
Intermediate
to Frequent
Variable absorption; drug-drug
interactions; decreased clearance
with renal failure
Uncertain reference
range
Stiripentol Frequent
Extensive first-pass metabolism,
high serum protein binding, zero-
order kinetics

Tiagabine Intermediate High serum protein binding
Uncertain reference
range
Topiramate Intermediate Variable metabolism
Valproic acid Frequent
Well-established therapeutic
range
Limited correlation of
plasma concentration
and efficacy
Vigabatrin Uncommon Irreversible action
Zonisamide Frequent
Variable metabolism, well-define
toxic range

Table 2. Summary of Justifications of TDM of AEMs
www.intechopen.com

Therapeutic Drug Monitoring of Antiepileptic Medications

147
5.14 Zonisamide
Zonisamide is approved in the United States for adjunctive treatment of partial seizures but
is also used off-label for bipolar disorder and migraine headaches (Leppik, 1999; Mimaki,
1998). After oral administration, zonisamide is rapidly absorbed and is only approximately
50% bound to serum proteins. Zonisamide is extensively metabolized by acetylation,
oxidation, and other enzymatic pathways (Buchanan et al., 1996). CYP3A4 is responsible for
some of the metabolism of zonisamide. Consequently, the metabolism of zonisamide can be
significantly affected by CYP inducers and inhibitors. The elimination half-life of
zonisamide is approximately 50-70 hr for patients receiving zonisamide as monotherapy but
decreases to 25-35 hr in patients concomitantly taking enzyme inducers such as
carbamazepine or phenobarbital. On the other hand, liver enzyme inhibitors such as
ketoconazole and valproic acid may prolong zonisamide half-life (Perucca & Bialer, 1996).
Zonisamide is cleared effectively by hemodialysis (Ijiri et al., 2004). In general, children
require higher doses by weight than adults (Perucca, 2006). A serum/plasma reference
range of 10-40 mg/L has been proposed for seizure management (Glauser & Pippenger,
2000; Mimaki, 1998). Toxic side effects are uncommon at serum concentrations below 30
mg/L (Miura, 1993). The main reason to perform TDM for zonisamde is inter-individual
variability in metabolism, particularly in patients concomitantly taking CYP enzyme
inducers or inhibitors.
6. Conclusion
TDM has traditionally been applied to the first generation AEMs such as carbamazepine,
phenobarbital, phenytoin, and valproic acid, mainly due to the challenging pharmacokinetics
of this group of drugs. The newer generation AEMs generally have more favorable
pharmacokinetics and fewer adverse effects. The strongest evidence for routine TDM for the
new generation AEMs are for lamotrigine, oxcarbazepine (10-hydroxycarbazepine metabolite),
stiripentol, tiagabine, and zonisamide. For other AEMs, TDM may have value in adjusting
dosing for organ failure or to assess compliance with therapy. Future research is needed to
better delineate reference ranges and to establish the benefit of TDM in clinical practice.
7. References
Acharya, NV, Pickering, RM, Wilton, LW, Shakir, SA. (2005). The safety and effectiveness of
newer antiepileptics: a comparative postmarketing cohort study. Journal of Clinical
Pharmacology. Vol. 45, No. 4., (Apr 2005) 385-393. Print ISSN 0091-2700
al Za'abi, M, Deleu, D, Batchelor, C. (2003). Salivary free concentrations of anti-epileptic
drugs: an evaluation in a routine clinical setting. Acta Neurologica Belgica. Vol. 103,
No. 1. (Mar 2003) 19-23. Print ISSN 0300-9009
Alfirevic, A, Jorgensen, AL, Williamson, PR, Chadwick, DW, Park, BK, Pirmohamed, M.
(2006). HLA-B locus in Caucasian patients with carbamazepine hypersensitivity.
Pharmacogenomics. Vol. 7, No. 6. (Sep 2006) 813-818. Print ISSN 1462-2416
Almeida, L, Falcao, A, Maia, J, Mazur, D, Gellert, M, Soares-da-Silva, P. (2005). Single-dose
and steady-state pharmacokinetics of eslicarbazepine acetate (BIA 2-093) in healthy
elderly and young subjects. Journal of Clinical Pharmacology. Vol. 45, No. 9. (Sep
2005) 1062-1066. Print ISSN 0091-2700
www.intechopen.com

Novel Treatment of Epilepsy

148
Almeida, L, Nunes, T, Sicard, E, Rocha, JF, Falcao, A, Brunet, JS, Lefebvre, M, Soares-da-
Silva, P. (2010). Pharmacokinetic interaction study between eslicarbazepine acetate
and lamotrigine in healthy subjects. Acta Neurologica Scandinavica. Vol. 121, No. 4.
(Dec 2010) 257-264. Print ISSN 1600-0404
Almeida, L, Potgieter, JH, Maia, J, Potgieter, MA, Mota, F, Soares-da-Silva, P. (2008).
Pharmacokinetics of eslicarbazepine acetate in patients with moderate hepatic
impairment. European Journal of Clinical Pharmacology. Vol. 64, No. 3. (Mar 2008) 267-
273. Print ISSN 0031-6970
Alves, G, Figueiredo, I, Castel-Branco, M, Loureiro, A, Fortuna, A, Falcao, A, Caramona, M.
(2007). Enantioselective HPLC-UV method for determination of eslicarbazepine
acetate (BIA 2-093) and its metabolites in human plasma. Biomedical
Chromatography. Vol. 21, No. 11. (Nov 2007) 1127-1134. Print ISSN 0269-3879
Armijo, JA, Perna, MA, Adin, J, Vega-Gil, N. (2004). Association between patient age and
gabapentin serum concentration-to-dose ratio: a preliminary multivariate analysis.
Therapeutic Drug Monitoring. Vol. 26, No. 6. 633-637. (Dec 2004) Print ISSN 0163-
4356
Bartoli, A, Guerrini, R, Belmonte, A, Alessandri, MG, Gatti, G, Perucca, E. (1997). The
influence of dosage, age, and comedication on steady state plasma lamotrigine
concentrations in epileptic children: a prospective study with preliminary
assessments of correlations with clinical response. Therapeutic Drug Monitoring. Vol.
19, No. 3. (Jun 1997) 252-260. Print ISSN 0163-4356
Battino, D, Estienne, M, Avanzini, G. (1995). Clinical pharmacokinetics of antiepileptic drugs
in pediatric patients. Part II. Phenytoin, carbamazepine, sulthiame, lamotrigine,
vigabatrin, oxcarbazepine and felbamate. Clinical Pharmacokinetics Vol. 29, No. 5.
(Nov 1995) 341-369. Print ISSN 0312-5963
Ben-Menachem, E, Biton, V, Jatuzis, D, Abou-Khalil, B, Doty, P, Rudd, GD. (2007). Efficacy
and safety of oral lacosamide as adjunctive therapy in adults with partial-onset
seizures. Epilepsia. Vol. 48, No. 7. (Jul 2007) 1308-1317. Print ISSN 0013-9580
Benetello, P, Furlanut, M, Fortunato, M, Baraldo, M, Pea, F, Tognon, A, Testa, G. (1997). Oral
gabapentin disposition in patients with epilepsy after a high-protein meal. Epilepsia.
Vol. 38, No. 10. (Oct 1997) 1140-1142. Print ISSN 0013-9580
Berry, DJ, Beran, RG, Plunkeft, MJ, Clarke, LA, Hung, WT. (2003). The absorption of
gabapentin following high dose escalation. Seizure. Vol. 12, No. 1. (Jan 2003) 28-36.
Print ISSN 1059-1311
Besag, FM, Berry, D. (2006). Interactions between antiepileptic and antipsychotic drugs.
Drug Safety. Vol. 29, No. 2. (2006) 95-118. Print ISSN 0114-5916
Besag, FM, Berry, DJ, Pool, F. (1998). Carbamazepine toxicity with lamotrigine:
pharmacokinetic or pharmacodynamic interaction. Epilepsia. Vol. 39, No. 2. (Feb
1998) 183-187. Print ISSN 0013-9580
Beydoun, A, D'Souza, J, Hebert, D, Doty, P. (2009). Lacosamide: pharmacology, mechanisms
of action and pooled efficacy and safety data in partial-onset seizures. Expert Review
of Neurotherapeutics. Vol. 9, No. 1. (Jan 2009) 33-42. Print ISSN 1744-8360
Bialer, M. (2005). The pharmacokinetics and interactions of new antiepileptic drugs: an
overview. Therapeutic Drug Monitoring. Vol. 27, No. 6. (Dec 2005) 722-726. Print
ISSN 0163-4356
Bialer, M, Johannessen, SI, Levy, RH, Perucca, E, Tomson, T, White, HS. (2009). Progress
report on new antiepileptic drugs: a summary of the Ninth Eilat Conference
(EILAT IX). Epilepsy Research. Vol. 83, No. 1. (Jan 2009) 1-43. Print ISSN 1872-6844
www.intechopen.com

Therapeutic Drug Monitoring of Antiepileptic Medications

149
Biton, V. (2006). Pharmacokinetics, toxicology and safety of lamotrigine in epilepsy. Expert
Opinion in Drug Metabolism and Toxicology. Vol. 2, No. 6. (Dec 2006) 1009-1018. Print
ISSN 1742-5255
Bockbrader, HN, Hunt, T, Strand, J, Posvar, EL, Sedman, A. (2000). Pregabalin
pharmacokinetics and safety in health volunteers: results from two phase I studies.
Neurology. Vol. 11, Suppl 3. (2000) 412. Electronic ISSN 1526-632X
Bourgeois, BF. (1997). Felbamate. Seminars in Pediatric Neurology. Vol. 4, No. 1. (Mar 1997) 3-
8. Print ISSN 1071-9091
Britzi, MP, E., Soback, S, Levy, RH, Fattore, C, Crema, F, Gatti, G, Doose, DR, Maryanoff, BE,
Bialer, M. (2005). Pharmacokinetic and metabolic investigation of topiramate
disposition in healthy subjects in the absence and in the presence of enzyme
induction by carbamazepine. Epilepsia. Vol. 46, No. 3. (Mar 2005) 378-384. Print
ISSN 0013-9580
Brodie, MJ, Dichter, MA. (1997). Established antiepileptic drugs. Seizure. Vol. 6, No. 3. (Jun
1997) 159-174. Print ISSN 1059-1311
Buchanan, R, Bockbrader, HN, Chang, T, Sedman, AJ. (1996). Single- and multiple-dose
pharmacokinetics of zonisamide. Epilepsia. Vol. 37, No. Suppl 5. (1996) 172. Print
ISSN 0013-9580
Busch, JA, Strand, JC, Posvar, EL, Bockbrader, HN, Radulovic, LL. (1998). Pregabalin (CI-
1008) single-dose pharmacokinetics and safety/tolerance in healthy subjects after
oral administration of pregabalin solution or capsule doses. Epilepsia. Vol. 39, No.
Suppl 6. (1998) 58. Print ISSN 0013-9580
Cardot, JM, Degen, P, Flesch, G, Menge, P, Dieterle, W. (1995). Comparison of plasma and
saliva concentrations of the active monohydroxy metabolite of oxcarbazepine in
patients at steady state. Biopharmaceutics & Drug Disposition. Vol. 16, No. 7. (Oct
1995) 603-614. Print ISSN 0142-2782
Cato, A, 3rd, Gustavson, LE, Qian, J, El-Shourbagy, T, Kelly, EA. (1998). Effect of renal
impairment on the pharmacokinetics and tolerability of tiagabine. Epilepsia. Vol. 39,
No. 1. (Jan 1998) 43-47. Print ISSN 0013-9580
Christensen, J, Sabers, A, Sidenius, P. (2006). Oxcarbazepine concentrations during
pregnancy: a retrospective study in patients with epilepsy. Neurology. Vol. 24, No.
8. (Aug 2006) 1497-1499. Electronic ISSN 1526-632X
Chung, S, Sperling, MR, Biton, V, Krauss, G, Hebert, D, Rudd, GD, Doty, P. (2010).
Lacosamide as adjunctive therapy for partial-onset seizures: A randomized
controlled trial. Epilepsia. Vol. 51, No. 6 (June 2010) Print ISSN 0013-9580
Corrigan, BW, Poole, WF, Posvar, EL, Strand, JC, Alvey, CW, Radulovic, LL. (2001).
Metabolic disposition of pregabalin in healthy volunteers. Clinical Pharmacology and
Therapeutics. Vol. 69, Suppl. (2001) P18. Print ISSN 0009-9236
Crawford, P. (2002). Interactions between antiepileptic drugs and hormonal contraception.
CNS Drugs. Vol. 16, No. 4. (Apr 2002) 263-272. Print ISSN 1172-7047
Cross, SA, Curran, MP. (2009). Lacosamide: in partial-onset seizures. Drugs. Vol. 69, No. 4.
(Apr 2009) 449-459. Print ISSN 0012-6667
Curia, G, Biagini, G, Perucca, E, Avoli, M. (2009). Lacosamide: a new approach to target
voltage-gated sodium currents in epileptic disorders. CNS Drugs. Vol. 23, No. 7. (Jul
2009) 555-568. Print ISSN 1172-7047
Dasgupta, A. (2007). Usefulness of monitoring free (unbound) concentrations of therapeutic
drugs in patient management. Clinica Chimca Acta. Vol. 377, No. 1-2. (Feb 2007) 1-
13. Print ISSN 009-8981
www.intechopen.com

Novel Treatment of Epilepsy

150
Durham, SL, Hoke, JF, Chen, TM. (1993). Pharmacokinetics and metabolism of vigabatrin
following a single oral dose of [
14
C]vigabatrin in healthy male volunteers. Drug
Metabolism and Disposition. Vol. 21, No. 3. (May-Jun 1993) 480-484. Print ISSN 0090-
9556
Easterling, DE, Zakszewski, T, Moyer, MD, Margul, BL, Marriott, TB, Nayak, RK. (1988).
Plasma pharmacokinetics of topiramate, a new anticonvulsants in humans.
Epilepsia. Vol. 29, Suppl. (1988) Print ISSN 0013-9580
Eckardt, KM, Steinhoff, BJ. (1998). Nonconvulsive status epilepticus in two patients
receiving tiagabine treatment. Epilepsia. Vol. 39, No. 6. (Jun 1998) 671-674. Print
ISSN 0013-9580
Falcao, A, Maia, J, Almeida, L, Mazur, D, Gellert, M, Soares-da-Silva, P. (2007). Effect of
gender on the pharmacokinetics of eslicarbazepine acetate (BIA 2-093), a new
voltage-gated sodium channel blocker. Biopharmaceutics & Drug Disposition. Vol. 28,
No. 5. (Jul 2007) 249-256. Print ISSN 0142-2782
Farwell, JR, Anderson, GD, Kerr, BM, Tor, JA, Levy, RH. (1993). Stiripentol in atypical
absence seizures in children: an open trial. Epilepsia. Vol. 34, No. 2. (Mar-Apr 1993)
305-311. Print ISSN 0013-9580
Faught, E, Sachdeo, RC, Remler, MP, Chayasirisobhon, S, Iragui-Madoz, VJ, Ramsay, RE,
Sutula, TP, Kanner, A, Harner, RN, Kuzniecky, R, Kramer, LD, Karmin, M,
Rosenberg, A. (1993). Felbamate monotherapy for partial-onset seizures: an active-
controlled trial. Neurology. Vol. 43, No. 4. (Apr 1993) 688-692. Electronic ISSN 1526-
632X
Fay, MA, Sheth, RD, Gidal, BE. (2005). Oral absorption kinetics of levetiracetam: the effect of
mixing with food or enteral nutrition formulas. Clinical Therapeutics. Vol. 27, No. 5.
(May 2005) 594-598. Print ISSN 0149-2918
Fillastre, JP, Taburet, AM, Fialaire, A, Etienne, I, Bidault, R, Singlas, E. (1993).
Pharmacokinetics of lamotrigine in patients with renal impairment: influence of
haemodialysis. Drugs Under Experimental and Clinical Research. Vol. 19, No. 1. (Jan
1993) 25-32. Print ISSN 0378-6501
Friis, ML, Kristensen, O, Boas, J, Dalby, M, Deth, SH, Gram, L, Mikkelsen, M, Pedersen, B,
Sabers, A, Worm-Petersen, J. (1993). Therapeutic experiences with 947 epileptic out-
patients in oxcarbazepine treatment. Acta Neurologica Scandanavica. Vol. 87, No. 3.
(Mar 1993) 224-227. Print ISSN 0001-6314
Frscher, W, Eichelbaum, M, Gugler, R, Hildebrand, G, Penin, H. (1981). A prospective
randomized trial on the effect of monitoring plasma anticonvulsant levels in
epilepsy. Journal of Neurology. Vol. 224, No. 3. (Mar 1981) 193-201. Print ISSN 0340-
5354
Gidal, BE, DeCerce, J, Bockbrader, HN, Gonzalez, J, Kruger, S, Pitterle, ME, Rutecki, P,
Ramsay, RE. (1998). Gabapentin bioavailability: effect of dose and frequency of
administration in adult patients with epilepsy. Epilepsy Research. Vol. 31, No. 2. (Jul
1998) 91-99. Print ISSN 0920-1211
Glauser, TA, Pippenger, CE. (2000). Controversies in blood-level monitoring: re-examining
its role in the treatment of epilepsy. Epilepsia. Vol. 41, Suppl 8. (2000) S6-S15. Print
ISSN 0013-9580
Grim, SA, Ryan, M, Miles, MV, Tang, PH, Strawsburg, RH, de Grauw, TJ, Fakhoury, TA,
Baumann, RJ. (2003). Correlation of levetiracetam concentrations between serum
and plasma. Therapeutic Drug Monitoring. Vol. 25, No. 1. (Dec 2003) 61-66. Print
ISSN 0277-0008
www.intechopen.com

Therapeutic Drug Monitoring of Antiepileptic Medications

151
Guo, T, Oswald, LM, Mendu, DR, Soldin, SJ. (2007). Determination of levetiracetam in
human plasma/serum/saliva by liquid chromatography-electrospray tandem mass
spectrometry. Clinica Chimica Acta. Vol. 375, No. 1-2. (Jan 2007) 115-118. Print ISSN
0009-8981
Gustavson, LE, Boellner, SW, Granneman, GR, Qian, JX, Guenther, HJ, el-Shourbagy, T,
Sommerville, KW. (1997). A single-dose study to define tiagabine pharmacokinetics
in pediatric patients with complex partial seizures. Neurology. Vol. 48, No. 4. (Apr
1997) 1032-1037. Electronic ISSN 1526-632X
Gustavson, LE, Mengel, HB. (1995). Pharmacokinetics of tiagabine, a g-aminobutyric acid-
uptake inhibitor, in healthy subjects after single and multiple doses. Epilepsia. Vol.
36, No. 6. (Jun 1995) 605-611. Print ISSN 0013-9580
Hakimian, S, Cheng-Hakimian, A, Anderson, GD, Miller, JW. (2007). Rufinamide: a new
anti-epileptic medication. Expert Opinion on Pharmacotherapy. Vol. 8, No. 12. (Aug
2007) 1931-1940. Print ISSN 1744-7666
Hardman JG, Limbird LE, Molinoff PB, Ruddon RW, Gilman AG. (1996). Pharmacokinetic
data, In: Goodman & Gilman's The Pharmacological Basis of Therapeutics, Hardman JG,
Limbird LE, Molinoff PB, Ruddon RW, Gilman AG (eds), pp. 1712-1792, McGraw-
Hill, ISBN 0-070-026266-7, New York.
Heaney, D, Walker, MC. (2007). Rufinamide. Drugs Today (Barcelona). Vol. 43, No. 7. (Jul
2007) 455-460. Print ISSN 1699-3993
Hung, TY, Seow, VK, Chong, CF, Wang, TL, Chen, CC. (2008). Gabapentin toxicity: an
important cause of altered consciousness in patients with uraemia. Emergency
Medicine Journal. Vol. 25, No. 3. (Mar 2008) 178-179. Print ISSN 1472-0213
Hussein, Z, Posner, J. (1997). Population pharmacokinetics of lamotrigine monotherapy in
patients with epilepsy: retrospective analysis of routine monitoring data. British
Journal of Clinical Pharmacology. Vol. 43, No. 5. (May 1997) 457-464. Print ISSN 0306-
5251
Ijiri, Y, Inoue, T, Fukuda, F, Suzuki, K, Kobayashi, T, Shibahara, N, Takenaka, H, Tanaka, K.
(2004). Dialyzability of the antiepileptic drug zonisamide in patients undergoing
hemodialysis. Epilepsia. Vol. 45, No. 8. (Aug 2004) 924-927. Print ISSN 0013-9580
Incecayir, T, Agabeyoglu, I, Gucuyener, K. (2007). Comparison of plasma and saliva
concentrations of lamotrigine in healthy volunteers. Arzneimittelforschung. Vol. 57,
No. 8. (Aug 2007) 517-521. Print ISSN 0004-4172
Jacqz-Aigrain, E, Guillonneau, M, Rey, E, Macher, MA, Montes, C, Chiron, C, Loirat, C.
(1997). Pharmacokinetics of the S(+) and R(-) enantiomers of vigabatrin during
chronic dosing in a patient with renal failure. British Journal of Clinical Pharmacology.
Vol. 44, No. 2. (Aug 1997) 183-185. Print ISSN 0306-5251
Januzzi, G, Cian, P, Fattore, C, Gatti, G, Bartoli, A, Monaco, F, Perucca, E. (2000). A
multicenter randomized controlled trial on the clinical impact of therapeutic drug
monitoring in patients with newly diagnosed epilepsy. Epilepsia. Vol. 41, No. 2. (Feb
2000) 222-230. Print ISSN 0013-9580
Johannessen Landmark, C. (2008). Antiepileptic drugs in non-epilepsy disorders: relations
between mechanisms of action and clinical efficacy. CNS Drugs. Vol. 22, No. 1. (Jan
2008) 27-47. Print ISSN 1172-7047
Johannessen Landmark, C, Patsalos, PN. (2010). Drug interactions involving the new
second- and third-generation antiepileptic drugs. Expert Review of Neurotherapeutics.
Vol. 10, No. 1. (Jan 2010) 119-140. Print ISSN 1744-8360
www.intechopen.com

Novel Treatment of Epilepsy

152
Johannessen, SI, Battino, D, Berry, DJ, Bialer, M, Kramer, G, Tomson, T, Patsalos, PN. (2003).
Therapeutic drug monitoring of the newer antiepileptic drugs. Therapeutic Drug
Monitoring. Vol. 25, No. 3. (Mar 2003) 347-363. Print ISSN 0277-0008
Jones, MD, Ryan, M, Miles, MV, Tang, PH, Fakhoury, TA, Degrauw, TJ, Baumann, RJ.
(2005). Stability of salivary concentrations of the newer antiepileptic drugs in the
postal system. Therapeutic Drug Monitoring. Vol. 27, No. 5. (Oct 2005) 576-579. Print
0163-4356
Kellinghaus, C. (2009). Lacosamide as treatment for partial epilepsy: mechanisms of action,
pharmacology, effects, and safety. Therapeutics and Clinical Risk Management. Vol. 5,
(2009) 757-766. Print ISSN 1176-6336
Kellinghaus, C, Dziewas, R, Ludemann, P. (2002). Tiagabine-related non-convulsive status
epilepticus in partial epilepsy: three case reports and a review of the literature.
Seizure. Vol. 11, No. 4. (Jun 2002) 243-249. Print ISSN 1059-1311
Klitgaard, H. (2001). Levetiracetam: the preclinical profile of a new class of antiseizure
drugs? Epilepsia. Vol. 42, Suppl 4. (2001) S13-S18. Print ISSN 0013-9580
Knowles, SR, Shapiro, LE, Shear, NH. (1999). Anticonvulsant hypersensitivity syndrome:
incidence, prevention and management. Drug Safety. Vol. 21, No. 6. (Dec 1999) 489-
501. Print ISSN 0114-5916
Komoroski, BJ, Zhang, S, Cai, H, Hutzler, JM, Frye, R, Tracy, TS, Strom, SC, Lehmann, T,
Ang, CYW, Cui, YY, Venkataramanan, R. (2004). Induction and inhibition of
cytochromes P450 by the St. John's wort constituent hyperforin in human
hepatocyte cultures. Drug Metabolism and Disposition. Vol. 32, No. 5. (May 2004) 512-
518. Print ISSN 0090-9556
Kristensen, O, Klitgaard, NA, Jonsson, B, Sindrup, S. (1983). Pharmacokinetics of 10-OH-
carbazepine, the main metabolite of the antiepileptic oxcarbazepine, from serum
and saliva concentrations. Acta Neurologica Scandinavica. Vol. 68, No. 3. (Sep 1983)
145-150. Print ISSN 0001-6314
Kumagai, N, Seki, T, Yamada, T, Takuma, Y, Hirai, K. (1993). Concentrations of zonisamide
in serum, free fraction, mixed saliva and cerebrospinal fluid in epileptic children
treated with monotherapy. The Japanese Journal of Psychiatry and Neurology. Vol. 47,
No. 2. (Jun 1993) 291-292. Print ISSN 0912-2036
Lacerda, G, Krummel, T, Sabourdy, C, Ryvlin, P, Hirsch, E. (2006). Optimizing therapy of
seizures in patients with renal or hepatic dysfunction. Neurology. Vol. 67, No. 12
Suppl 4. (Dec 2006) S28-33. Electronic ISSN 1526-632X
Larkin, JG, McKee, PJ, Forrest, G, Beastall, GH, Park, BK, Lowrie, JI, Lloyd, P, Brodie, MJ.
(1991). Lack of enzyme induction with oxcarbazepine (600 mg daily) in healthy
subjects. British Journal of Clinical Pharmacology. Vol. 31, No. 1. (Jan 1991) 65-71.
Print ISSN 0306-5251
LaRoche, SM, Helmers, SL. (2004a). The new antiepileptic drugs: clinical applications.
JAMA. Vol. 291, No. 5. (Feb 2004) 615-620. Print ISSN 0098-7484
LaRoche, SM, Helmers, SL. (2004b). The new antiepileptic drugs: scientific review. JAMA.
Vol. 291, No. 5. (Feb 2004) 605-614. Print ISSN 0098-7484
Lau, AH, Gustavson, LE, Sperelakis, R, Lam, NP, El-Shourbagy, T, Qian, JX, Layden, T.
(1997). Pharmacokinetics and safety of tiagabine in subjects with various degrees of
hepatic function. Epilepsia. Vol. 38, No. 4. (Apr 1997) 445-451. Print ISSN 0013-9580
Leppik, IE. (1999). Zonisamide. Epilepsia. Vol. 40, Suppl 5. (1999) S23-S29. Print ISSN 0013-
9580
www.intechopen.com

Therapeutic Drug Monitoring of Antiepileptic Medications

153
Leppik, IE. (2001). The place of levetiracetam in the treatment of epilepsy. Epilepsia. Vol. 42,
No. Suppl 4. (2001) S44-S45. Print ISSN 0013-9580
Leppik, IE, Rarick, JO, Walczak, TS, Tran, TA, White, JR, Gumnit, RJ. (2002). Effective
levetiracetam doses and serum concentrations: age effects. Epilepsia. Vol. 43, Suppl
7. (2002) 240. Print ISSN 0013-9580
Levy, RH, Lin, HS, Blehaut, HM, Tor, JA. (1983). Pharmacokinetics of stiripentol in normal
man: evidence of nonlinearity. Journal of Clinical Pharmacology. Vol. 23, No. 11-12.
(Nov-Dec 1983) 523-533. Print ISSN
Levy, RH, Loiseau, P, Guyot, M, Blehaut, HM, Tor, J, Moreland, TA. (1984). Stiripentol
kinetics in epilepsy: nonlinearity and interactions. Clinical Pharmacology and
Therapeutics. Vol. 36, No. 5. (Nov 1984) 661-669. Print ISSN 0009-9236
Lindberger, M, Luhr, O, Johannessen, SI, Larsson, S, Tomson, T. (2003). Serum
concentrations and effects of gabapentin and vigabatrin: observations from a dose
titration study. Therapeutic Drug Monitoring. Vol. 25, No. 4. (Apr 2003) 457-462. Print
ISSN 0277-0008
Lins, RL, Otoul, C, De Smedt, F, Coupez, R, Stockis, A. (2007). Comparison of plasma and
saliva concentrations of levetiracetam following administration orally as a tablet
and as a solution in healthy adult volunteers. International Journal of Clinical
Pharmacology and Therapeutics. Vol. 45, No. 1. (Jan 2007) 47-54. Print ISSN 0946-1965
Liu, H, Delgado, MR. (1999). Therapeutic drug concentration monitoring using saliva
samples. Focus on anticonvulsants. Clinical Pharmacokinetics. Vol. 36, No. 6. (Jun
1999) 453-470. Print ISSN 0312-5963
Lloyd, P, Flesch, G, Dieterle, W. (1994). Clinical pharmacology and pharmacokinetics of
oxcarbazepine. Epilepsia. Suppl 3 (1994) 10-13. Print ISSN 0013-9580
Lonjou, C, Thomas, L, Borot, N, Ledger, N, de Toma, C, LeLouet, H, Graf, E, Schumacher,
M, Hovnanian, A, Mockenhaupt, M, Roujeau, JC. (2006). A marker for Stevens-
Johnson syndrome ...: ethnicity matters. Pharmacogenomics Journal. Vol. 6, No. 4.
(Jul-Aug 2006) 265-268. Print ISSN 1470-269X
Luo, G, Guenthner, T, Gan, L-S, Humphreys, WG. (2004). CYP3A4 induction by xenobiotics:
biochemistry, experimental methods and impact on drug discovery and
development. Current Drug Metabolism. Vol. 5, No. 6. (Dec 2004) 483-505. Print
ISSN 1389-2002
Luszczki, JJ. (2009). Third-generation antiepileptic drugs: mechanisms of action,
pharmacokinetics and interactions. Pharmacological Reports. Vol. 61, No. 2. (Mar-Apr
2009) 197-216. Print ISSN 1734-1140
Maia, J, Almeida, L, Falcao, A, Soares, E, Mota, F, Potgieter, MA, Potgieter, JH, Soares-da-
Silva, P. (2008). Effect of renal impairment on the pharmacokinetics of
eslicarbazepine acetate. International Journal of Clinical Pharmacology and Therapeutics.
Vol. 46, No. 3. (Mar 2008) 119-130. Print ISSN 0946-1965
Maia, J, Vaz-da-Silva, M, Almeida, L, Falcao, A, Silveira, P, Guimaraes, S, Graziela, P,
Soares-da-Silva, P. (2005). Effect of food on the pharmacokinetic profile of
eslicarbazepine acetate (BIA 2-093). Drugs R D. Vol. 6, No. 4. (Apr 2005) 201-206.
Print ISSN 1174-5886
Malone, SA, Eadie, MJ, Addison, RS, Wright, AW, Dickinson, RG. (2006). Monitoring
salivary lamotrigine concentrations. Journal of Clinical Neuroscience. Vol. 13, No. 9.
(Nov 2006) 902-907. Print ISSN 0967-5868
www.intechopen.com

Novel Treatment of Epilepsy

154
May, TW, Korn-Merker, E, Rambeck, B. (2003). Clinical pharmacokinetics of oxcarbazepine.
Clinical Pharmacokinetics. Vol. 42, No. 12. (Dec 2003) 1023-1042. Print ISSN 0312-
5963
Mazzucchelli, I, Onat, FY, Ozkara, C, Atakli, D, Specchio, LM, Neve, AL, Gatti, G, Perucca,
E. (2006). Changes in the disposition of oxcarbazepine and its metabolites during
pregnancy and the puerperium. Epilepsia. Vol. 47, No. 3. (Mar 2006) 504-509. Print
ISSN 0013-9580
McLean, MJ. (1995). Gabapentin. Epilepsia. Vol. 36, Suppl 2. (1995) S57-S86. Print ISSN 0013-
9580
Mecarelli, O, Li Voti, P, Pro, S, Romolo, FS, Rotolo, M, Pulitano, P, Accornero, N, Vanacore,
N. (2007). Saliva and serum levetiracetam concentrations in patients with epilepsy.
Therapeutic Drug Monitoring. Vol. 29, No. 3. (Jun 2007) 313-318. Print ISSN 0163-
4356
Miles, MV, Tang, PH, Glauser, TA, Ryan, MA, Grim, SA, Strawsburg, RH, deGrauw, TJ,
Baumann, RJ. (2003). Topiramate concentration in saliva: an alternative to serum
monitoring. Pediatric Neurology. Vol. 29, No. 2. (Aug 2003) 143-147. Print ISSN 0887-
8994
Miles, MV, Tang, PH, Ryan, MA, Grim, SA, Fakhoury, TA, Strawsburg, RH, DeGrauw, TJ,
Baumann, RJ. (2004). Feasibility and limitations of oxcarbazepine monitoring using
salivary monohydroxycarbamazepine (MHD). Therapeutic Drug Monitoring. Vol. 26,
No. 3. (Jun 2004) 300-304. Print ISSN 0163-4356
Mimaki, T. (1998). Clinical pharmacology and therapeutic drug monitoring of zonisamide.
Therapeutic Drug Monitoring. Vol. 20, No. 6. (Jun 1998) 593-597. Print ISSN 0277-
0008
Miura, H. (1993). Developmental and therapeutic pharmacology of antiepileptic drugs. The
Japanese Journal of Psychiatry and Neurology. Vol. 47, No. 2. (Feb 1993) 169-174. Print
ISSN 0912-2036
Morris, RG, Black, AB, Harris, AL, Batty, AB, Sallustio, BC. (1998). Lamotrigine and
therapeutic drug monitoring: retrospective survey following the introduction of a
routine service. British Journal of Clinical Pharmacology. Vol. 46, No. 6. (Jun 1998) 547-
551. Print ISSN 0306-5251
Neels, HM, Sierens, AC, Naelerts, K, Scharp, SL, Hatfield, GM, Lambert, WE. (2004).
Therapeutic drug monitoring of old and newer anti-epileptic drugs. Clinical
Chemstry and Laboratory Medicine. Vol. 42, No. 11. (2004) 1228-1255. Print ISSN 1434-
6621
Ninomiya, H, Mamiya, K, Matsuo, S, Ieiri, I, Higuchi, S, Tashiro, N. (2000). Genetic
polymorphism of the CYP2C subfamily and excessive serum phenytoin
concentration with central nervous system intoxication. Therapeutic Drug
Monitoring. Vol. 22, No. 2. (Apr 2000) 230-232. Print 0163-4356
Patsalos, PN. (1999). New antiepileptic drugs. Annals of Clinical Biochemistry. Vol. 36, No. 1.
(Jan 1999) 10-19. Print ISSN 0004-5632
Patsalos, PN. (2000). Pharmacokinetic profile of levetiracetam: toward ideal characteristics.
Pharmacology and Therapeutics. Vol. 85, No. 2. (Feb 2000) 77-85. Print ISSN 0163-7258
Patsalos, PN. (2004). Clinical pharmacokinetics of levetiracetam. Clinical Pharmacokinetics.
Vol. 43, No. 11. (Nov 2004) 707-724. Print ISSN 0312-5963
Patsalos, PN, Berry, DJ, Bourgeois, BFD, Cloyd, JC, Glauser, TA, Johannessen, SI, Tomson, T,
Perucca, E. (2008). Antiepileptic drugs - best practice guidelines for therapeutic
drug monitoring: a position paper by the subcommission on therapeutic drug
www.intechopen.com

Therapeutic Drug Monitoring of Antiepileptic Medications

155
monitoring, ILAE Commission on Therapeutic Strategies. Epilepsia. Vol. 49, No. 7.
(Jun 2008) 1239-1276. Print ISSN 0013-9580
Patsalos, PN, Elyas, AA, Ratnaraj, N, Iley, J. (2002). Concentration-dependent displacement
of tiagabine by valproic acid. Epilepsia. Vol. 43, Suppl 8. (2002) 143. Print ISSN
0013-9580
Patsalos, PN, Ghattaura, S, Ratnaraj, N, Sander, JW. (2006). In situ metabolism of
levetiracetam in blood of patients with epilepsy. Epilepsia. Vol. 47, No. 11. (Nov
2006) 1818-1821. Print ISSN 0013-9580
Pellock, JM, Faught, E, Leppik, IE, Shinnar, S, Zupanc, ML. (2006). Felbamate: consensus of
current clinical experience. Epilepsy Research. Vol. 71, No. 2-3. (Oct 2006) 89-101.
Print ISSN 0920-1211
Pennell, PB, Peng, L, Newport, DJ, Ritchie, JC, Koganti, A, Holley, DK, Newman, M, Stowe,
ZN. (2008). Lamotrigine in pregnancy: clearance, therapeutic drug monitoring, and
seizure frequency. Neurology. Vol. 70, No. 22 Pt 2. (2008) 2130-2136. Electronic ISSN
1526-632X
Perucca, E. (1996). Established antiepileptic drugs. Baillieres Clinical Neurology. Vol. 5, No. 4.
(Dec 1996) 693-722. Print ISSN 0961-0421
Perucca, E. (2000). Is there a role for therapeutic drug monitoring of new anticonvulsants?
Clinical Pharmacokinetics. Vol. 38, No. 3. (Mar 2000) 191-204. Print ISSN 0312-5963
Perucca, E. (2006). Clinical pharmacokinetics of new-generation antiepileptic drugs at the
extremes of age. Clinical Pharmacokinetics Vol. 45, No. 4. 351-364. Print ISSN 0312-
5963
Perucca, E, Bialer, M. (1996). The clinical pharmacokinetics of the newer antiepileptic drugs.
Focus on topiramate, zonisamide and tiagabine. Clinical Pharmacokinetics Vol. 31,
No. 1. (Jan 1996) 29-46. Print ISSN 0312-5963
Perucca, E, Cloyd, J, Critchley, D, Fuseau, E. (2008a). Rufinamide: clinical pharmacokinetics
and concentration-response relationships in patients with epilepsy. Epilepsia. Vol.
49, No. 7. (Jul 2008) 1123-1141. Print 0013-9580
Perucca, E, Yasothan, U, Clincke, G, Kirkpatrick, P. (2008b). Lacosamide. Nature Reviews
Drug Discovery. Vol. 7, No. 12. (Dec 2008) 973-974. Print ISSN 1474-1784
Pitlick, WH, Levy, RH. (1977). Time-dependent kinetics I: Exponential autoinduction of
carbamazepine in monkeys. Journal of Pharmaceutical Sciences. Vol. 66, No. 5. (May
1977) 647-649. Print ISSN 0022-3549
Radtke, RA. (2001). Pharmacokinetics of levetiracetam. Epilepsia. Vol. 42, Suppl. (2001) 24-27.
Print ISSN 0013-9580
Rambeck, B, Wolf, P. (1993). Lamotrigine clinical pharmacokinetics. Clinical Pharmacokinetics
Vol. 25, No. 6. (Jun 1993) 433-443. Print ISSN 0312-5963
Ramsay, RE, Pellock, JM, Garnett, WR, Sanchez, RM, Valakas, AM, Wargin, WA, Lai, AA,
Hubbell, J, Chern, WH, Allsup, T, et al. (1991). Pharmacokinetics and safety of
lamotrigine (Lamictal) in patients with epilepsy. Epilepsy Research. Vol. 10, No. 2-3.
(Nov-Dec 1991) 191-200. Print ISSN 0920-1211
Randinitis, EJ, Posvar, EL, Alvey, CW, Sedman, AJ, Cook, JA, Bockbrader, HN. (2003).
Pharmacokinetics of pregabalin in subjects with various degrees of renal functions.
Journal of Clinical Pharmacology. Vol. 43, No. 3. (Mar 2003) 277-283. Print ISSN 0091-
2700
Reimers, A, Skogvoll, E, Sund, JK, Spigset, O. (2007). Lamotrigine in children and
adolescents: the impact of age on its serum concentrations and on the extent of
www.intechopen.com

Novel Treatment of Epilepsy

156
drug interactions. European Journal of Clinical Pharmacology. Vol. 63, No. 7. (Jul 2007)
687-692. Print ISSN 0031-6970
Rey, E, Pons, G, Olive, G. (1992). Vigabatrin. Clinical pharmacokinetics. Clinical
Pharmacokinetics. Vol. 23, No. 4. (Apr 1992) 267-278. Print ISSN 0312-5963
Riss, J, Cloyd, J, Gates, J, Collins, S. (2008). Benzodiazepines in epilepsy: pharmacology and
pharmacokinetics. Acta Neurologica Scandinavica. Vol. 118, No. 2. (Aug 2008) 69-86.
Print ISSN 1600-0404
Rosenfeld, WE, Doose, DR, Walker, SA, Baldassarre, JS, Reifer, RA. (1999). A study of
topiramate pharmacokinetics and tolerability in children with epilepsy. Pediatric
Neurology. Vol. 20, No. 5. (May 1999) 339-344. Print ISSN 0887-8994
Rouan, MC, Lecaillon, JB, Godbillon, J, Menard, F, Darragon, T, Meyer, P, Kourilsky, O,
Hillion, D, Aldigier, JC, Jungers, P. (1994). The effect of renal impairment on the
pharmacokinetics of oxcarbazepine and its metabolites. European Journal of Clinical
Pharmacology. Vol. 47, No. 2. (Feb 1994) 161-167. Print ISSN 0031-6970
Ruiz, ME, Conforti, P, Fagiolino, P, Volonte, MG. (2010). The use of saliva as a biological
fluid in relative bioavailability studies: comparison and correlation with plasma
results. Biopharmaceutics & Drug Disposition. Vol. 31, No. 8-9. (Nov 2010) 476-485.
Print ISSN 0142-2782
Ryan, M, Grim, SA, Miles, MV, Tang, PH, Fakhoury, TA, Strawsburg, RH, deGrauw, TJ,
Baumann, RJ. (2003). Correlation of lamotrigine concentrations between serum and
saliva. Pharmacotherapy. Vol. 23, No. 12. (Dec 2003) 1550-1557. Print ISSN 0277-0008
Sabers, A, Buchholt, JM, Uldall, P, Hansen, EL. (2001). Lamotrigine plasma levels reduced
by oral contraceptives. Epilepsy Research. Vol. 47, No. 1-2. (Nov 2001) 151-154. Print
ISSN 0920-1211
Sabers, A, Ohman, I, Christensen, J, Tomson, T. (2003). Oral contraceptives reduce
lamotrigine plasma levels. Neurology. Vol. 61, No. 4. (Aug 26 2003) 570-571.
Electronic ISSN 1526-632X
Sabers, A, Tomson, T. (2009). Managing antiepileptic drugs during pregnancy and lactation.
Current Opinion in Neurology. Vol. 22, No. 2. (Apr 2009) 157-161. Print ISSN 1473-
6551 (Electronic)
Sachdeo, RC, Kramer, LD, Rosenberg, A, Sachdeo, S. (1992). Felbamate monotherapy:
controlled trial in patients with partial onset seizures. Annals of Neurology. Vol. 32,
No. 3. (Sep 1992) 386-392. Print ISSN 0364-5134
Sachdeo, RC, Narang-Sachdeo, SKH, J.R., Dix, RK, Shumaker, RC, Perhach, JL, Rosenberg,
A. (1993). Steady-state pharmacokinetics and dose-proportionality of felbamate
after oral administration of 1200, 2400, and 3600 mg/day of felbamate. Epilepsia.
Vol. 34, Suppl 6. (1993) 80. Print ISSN 0013-9580
Sachdeo, RC, Sachdeo, SK, Walker, SA, Kramer, LD, Nayak, RK, Doose, DR. (1996). Steady-
state pharmacokinetics of topiramate and carbamazepine in patients with epilepsy
during monotherapy and concomitant therapy. Epilepsia. Vol. 37, No. 8. (Aug 1996)
774-480. Print ISSN 0013-9580
Schapel, G, Chadwick, D. (1996). Tiagabine and non-convulsive status epilepticus. Seizure.
Vol. 5, No. 2. (Jun 1996) 153-156. Print ISSN 1059-1311
Schechter, PJ. (1989). Clinical pharmacology of vigabatrin. British Journal of Clinical
Pharmacology. Vol. 27, Suppl 1. (1989) 19S-22S. Print ISSN 0306-5251
Selak, I. (2001). Pregabalin (Pfizer). Current Opinion in Investigational Drugs. Vol. 2, No. 6.
(Jun 2001) 828-834. Print ISSN 1472-4472
www.intechopen.com

Therapeutic Drug Monitoring of Antiepileptic Medications

157
Shumaker, RC, Fantel, C, Kelton, E, Wong, K, Weliky, I. (1990). Evaluation of the elimination
of (
14
C) felbamate in healthy men. Epilepsia. Vol. 31, Suppl. (1990) 642. Print ISSN
0013-9580
Sivenius, J, Klviinen, R, Ylinen, A, Riekkinen, P. (1991). A double-blind study of
gabapentin in the treatment of partial seizures. Epilepsia. Vol. 32, No. 4. (Apr 1991)
539-542. Print ISSN 0013-9580
Skolnick, JL, Stoler, BS, Katz, DB, Anderston, WH. (1976). Rifampin, oral contraceptives, and
pregnancy. JAMA. Vol. 236, No. 12. (Sep 1976) 1382. Print ISSN 0098-7484
So, EL, Wolff, D, Graves, NM, Leppik, IE, Cascino, GD, Pixton, GC, Gustavson, LE. (1995).
Pharmacokinetics of tiagabine as add-on therapy in patients taking enzyme-
inducing antiepilepsy drugs. Epilepsy Research. Vol. 22, No. 3. (Nov 1995) 221-226.
Print ISSN 0920-1211
Striano, S, Striano, P, Di Nocera, P, Italiano, D, Fasiello, C, Ruosi, P, Bilo, L, Pisani, F. (2006).
Relationship between serum mono-hydroxy-carbazepine concentrations and
adverse effects in patients with epilepsy on high-dose oxcabazepine therapy.
Epilepsy Research. Vol. 69, No. 2. (Jun 2006) 170-176. Print ISSN 0920-1211
Tennison, M, Ali, I, Miles, MV, D'Cruz, O, Vaughn, B, Greenwood, R. (2004). Feasibility and
acceptance of salivary monitoring of antiepileptic drugs via the US Postal Service.
Therapeutic Drug Monitoring. Vol. 26, No. 3. (Jun 2004) 295-299. Print ISSN 0163-
4356
Thomas, D, Schartenecker, U, Nickel, B, Doty, P, Cawello, W, Horstmann, R. (2006). Low
potential for drug-drug interaction of lacosamide. Epilepsia. Vol. 47 Suppl, (2006)
200. Print ISSN 0013-9580
Thompson, CD, Barthen, MT, Hopper, DW, Miller, TA, Quigg, M, Hudspeth, C, Montouris,
G, Marsh, L, Perhach, JL, Sofia, RD, Macdonald, TL. (1999). Quantification in
patient urine samples of felbamate and three metabolites: acid carbamate and two
mercapturic acids. Epilepsia. Vol. 40, No. 6. (Jun 1999) 769-776. Print ISSN 0013-9580
Tomson, T, Battino, D. (2007). Pharmacokinetics and therapeutic drug monitoring of newer
antiepileptic drugs during pregnancy and the puerperium. Clin Pharmacokinet. Vol.
46, No. 3. (Mar 2007) 209-219. Print ISSN 0312-5963
Tran, A, Rey, E, Pons, G, Rousseau, M, d'Athis, P, Olive, G, Mather, GG, Bishop, FE,
Wurden, CJ, Labroo, R, Trager, WF, Kunze, KL, Thummel, KE, Vincent, JC,
Gillardin, JM, Lepage, F, Levy, RH. (1997). Influence of stiripentol on cytochrome
P450-mediated metabolic pathways in humans: in vitro and in vivo comparison
and calculation of in vivo inhibition constants. Clinical Pharmacology and
Therapeutics. Vol. 62, No. 5. (Nov 1997) 490-504. Print ISSN 0009-9236
Tran, A, Vauzelle-Kervroedan, F, Rey, E, Pous, G, d'Athis, P, Chiron, C, Dulac, O, Renard, F,
Olive, G. (1996). Effect of stiripentol on carbamazepine plasma concentration and
metabolism in epileptic children. European Journal of Clinical Pharmacology. Vol. 50,
No. 6. (Jun 1996) 497-500. Print ISSN 0031-6970
Tsiropoulos, I, Kristensen, O, Klitgaard, NA. (2000). Saliva and serum concentration of
lamotrigine in patients with epilepsy. Therapeutic Drug Monitoring. Vol. 22, No. 5.
(Oct 2000) 517-521. Print ISSN 0163-4356
Uthman, BM, Rowan, AJ, Ahmann, PA, Leppik, IE, Schachter, SC, Sommerville, KW, Shu, V.
(1998). Tiagabine for complex partial seizures: a randomized, add-on, dose-
response trial. Archives of Neurology. Vol. 55, No. 1. (Jan 1998) 56-62. Print ISSN
0003-9942
www.intechopen.com

Novel Treatment of Epilepsy

158
Van Buren, D, Wideman, CA, Ried, M, Gibbons, S, Van Buren, CT, Jarowenko, M, Flechner,
SM, Frazier, OH, Cooley, DA, Kahan, BD. (1984). The antagonistic effect of rifampin
upon cyclosporine bioavailability. Transplantation Proceedings. Vol. 16, No. 6. (Dec
1984) 1642-1645. Print ISSN 0041-1345
Vollmer, KO, von Hodenberg, A, Klle, EU. (1988). Pharmacokinetics and metabolism of
gabapentin in rat, dog and man. Arzneimittelforschung. Vol. 36, No. 5. (May 1988)
830-839. Print ISSN 0004-4172
Wagner, ML, Graves, NM, Marienau, K, Holmes, GB, Remmel, RP, Leppik, IE. (1991).
Discontinuation of phenytoin and carbamazepine in patients receiving felbamate.
Epilepsia. Vol. 32, No. 3. (May-Jun 1991) 398-406. Print ISSN 0013-9580
Ward, DL, Wagner, ML, Perhach, JL, Kramer, L, Graves, N, Leppik, I, Shumaker, RC. (1991).
Felbamate steady-state pharmacokinetics during co-administration of valproate.
Epilepsia. Vol. 32, Suppl 3. (1991) 8. Print ISSN 0013-9580
Warner, A, Privitera, M, Bates, D. (1998). Standards of laboratory practice: antiepileptic drug
monitoring. National Academy of Clinical Biochemistry. Clinical Chemistry. Vol. 44,
No. 5. (May 1998) 1085-1095. Print ISBN 0009-9147
Wheless, JW, Vazquez, B. (2010). Rufinamide: a novel broad-spectrum antiepileptic drug.
Epilepsy Currents. Vol. 10, No. 1. (Jan 2010) 1-6. Print ISSN 1535-7511
Williams, J, Bialer, M, Johannessen, SI, Krmer, G, Levy, R, Mattson, RH, Perucca, E,
Patsalos, PN, Wilson, JF. (2003). Interlaboratory variability in the quantification of
new generation antiepileptic drugs based on external quality assessment data.
Epilepsia. Vol. 44, No. 1. (Jan 2003) 40-45. Print ISSN 0013-9580
Wisniewski, CS. (2010). Rufinamide: a new antiepileptic medication for the treatment of
seizures associated with lennox-gastaut syndrome. Annals of Pharmacotherapy. Vol.
44, No. 4. (Apr 2010) 658-667. Print ISSN 1542-6270
Wong, MO, Eldon, MA, Keane, WF, Turck, D, Bockbrader, HN, Underwood, BA, Sedman,
AJ, Halstenson, CE. (1995). Disposition of gabapentin in anuric subjects on
hemodialysis. Journal of Clinical Pharmacology. Vol. 35, No. 6. (Jun 1995) 622-626.
Print ISBN 0091-2700
Yoo, L, Matalon, D, Hoffman, RS, Goldfarb, DS. (2009). Treatment of pregabalin toxicity by
hemodialysis in a patient with kidney failure. American Journal of Kidney Disease.
Vol. 54, No. 6. (Dec 2009) 1127-1130. Print ISSN 1523-6838
Zhou, C, Assem, M, Tay, JC, Watkins, PB, Blumberg, B, Schuetz, EG, Thummel, KE. (2006).
Steroid and xenobiotic receptor and vitamin D receptor crosstalk mediates CYP24
expression and drug-induced osteomalacia. Journal of Clinical Investigation. Vol. 116,
No. 6. (Jun 2006) 1703-1712. Print ISSN 0021-9738

www.intechopen.com
Novel Treatment of Epilepsy
Edited by Prof. Humberto Foyaca-Sibat
ISBN 978-953-307-667-6
Hard cover, 326 pages
Publisher InTech
Published online 22, September, 2011
Published in print edition September, 2011
InTech Europe
University Campus STeP Ri
Slavka Krautzeka 83/A
51000 Rijeka, Croatia
Phone: +385 (51) 770 447
Fax: +385 (51) 686 166
www.intechopen.com
InTech China
Unit 405, Office Block, Hotel Equatorial Shanghai
No.65, Yan An Road (West), Shanghai, 200040, China
Phone: +86-21-62489820
Fax: +86-21-62489821
Epilepsy continues to be a major health problem throughout the planet, affecting millions of people, mainly in
developing countries where parasitic zoonoses are more common and cysticercosis, as a leading cause, is
endemic. There is epidemiological evidence for an increasing prevalence of epilepsy throughout the world, and
evidence of increasing morbidity and mortality in many countries as a consequence of higher incidence of
infectious diseases, head injury and stroke. We decided to edit this book because we identified another way to
approach this problem, covering aspects of the treatment of epilepsy based on the most recent technological
results in vitro from developed countries, and the basic treatment of epilepsy at the primary care level in
rural areas of South Africa. Therefore, apart from the classic issues that cannot be missing in any book about
epilepsy, we introduced novel aspects related with epilepsy and neurocysticercosis, as a leading cause of
epilepsy in developing countries. Many experts from the field of epilepsy worked hard on this publication to
provide valuable updated information about the treatment of epilepsy and other related problems.
How to reference
In order to correctly reference this scholarly work, feel free to copy and paste the following:
Matthew D. Krasowski (2011). Therapeutic Drug Monitoring of Antiepileptic Medications, Novel Treatment of
Epilepsy, Prof. Humberto Foyaca-Sibat (Ed.), ISBN: 978-953-307-667-6, InTech, Available from:
http://www.intechopen.com/books/novel-treatment-of-epilepsy/therapeutic-drug-monitoring-of-antiepileptic-
medications