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Therapeutic drug monitoring of antiepileptic drugs: current status and future

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Article · February 2020

DOI: 10.1080/17425255.2020.1724956

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EXPERT OPINION ON DRUG METABOLISM & TOXICOLOGY
https://doi.org/10.1080/17425255.2020.1724956

REVIEW

Therapeutic drug monitoring of antiepileptic drugs: current status and future

prospects
Cecilie Johannessen Landmarka,b,c, Svein I. Johannessenb,c and Philip N. Patsalosd
a
Program for Pharmacy, Department of Life Sciences and Health, Faculty of Health Sciences, Metropolitan University, Oslo, Norway; bThe National
Center for Epilepsy, Sandvika, Oslo University Hospital, Oslo, Norway; cSection for Clinical Pharmacology, Department of Pharmacology, Oslo
University Hospital, Oslo, Norway; dDepartment of Clinical & Experimental Epilepsy, UCL Queen Square Institute of Neurology, London, UK

ABSTRACT ARTICLE HISTORY

Introduction: Antiepileptic drugs (AEDs) are the cornerstone of treatment of patients with epilepsy, and Received 13 November 2019
there are presently 27 licensed AEDs making AEDs among the most common medications for which Accepted 29 January 2020
therapeutic drug monitoring (TDM) is performed. The aim of this review is to provide an overview of the KEYWORDS
current evidence of the use and implementation of AED TDM in patients with epilepsy and other non- Antiepileptic drugs; epilepsy;
epilepsy conditions. drug interactions;
Areas covered: The pharmacokinetic variability of AEDs is extensive, resulting in pronounced variability pharmacokinetic variability;
in serum concentrations between patients. TDM may thus be useful to individualize the treatment of therapeutic drug monitoring
patients with epilepsy and also in non-epilepsy conditions. Indications for TDM include settings where
pharmacokinetic variability is anticipated (e.g. in children, the elderly, during pregnancy, and patients
prescribed polytherapy resulting in drug interactions) and drug adherence. TDM contributes to provide
a quality assurance of the treatment. Patient management is, therefore, best guided by the determina-
tion of individual therapeutic concentrations.
Expert opinion: Because of pharmacokinetic variability is prevalent among AEDs, TDM allows
a bespoke approach to epilepsy care allowing dose adjustments based on measured drug concentra-
tions so as to optimize clinical outcome. Future advances include the use of additional markers of
toxicity and genetic variability so as to further aid individualization and optimize AED treatment.

1. Introduction in a prolonged effect in the brain, even though the serum

concentration of vigabatrin is declining or even zero.
Therapeutic drug monitoring (TDM) is defined as the mea-
AEDs serve as the cornerstone of treatment of patients with
surement and clinical use of serum/plasma (or saliva) drug
epilepsy. In recent years, several new AEDs have been intro-
concentrations to adjust each patient’s individual dosage
duced to the market, and 27 AEDs are available internationally
and thus schedule to each patient’s individual therapeutic
[1]. For all AEDs, there is pronounced pharmacological varia-
requirement [1–8]. Although few randomized studies have
bility, where at present pharmacokinetic variability is most
demonstrated a positive impact of TDM on the clinical out-
easily measurable and might be controlled for [3,4].
come in epilepsy, evidence from non-randomized studies
Environmental, physiological, and genetic factors also contri-
and everyday clinical experience indicates that the use of
bute to extensive variability in the obtained serum concentra-
TDM for older as well as newer antiepileptic drugs (AEDs)
tions of any given AED. Also, aspects of adherence, if the drug
may best be used to guide patient management, provided
is taken as prescribed, come into play in the total evaluation of
that serum concentrations are measured with a clear indica-
the AED treatment.
tion and with a clinical interpretation [6]. AED TDM has
The onset of epilepsy is predominantly in early life, it is
been used to manage pharmacological variability in and
a chronic condition that often lasts for years or the whole life-
between patients for the last 50 years, and many drugs
time, and many patients require long-term therapy. The principal
have become available during that time, allowing continu-
outcome in epilepsy is the absence of seizures. Two-thirds of
ous development of this field of research and evaluating its
patients achieve seizure control with monotherapy AEDs, and
impact on clinical practice. TDM is relevant for all drugs
20–30% require polytherapy [2,9,10]. Furthermore, even though
where the serum concentration is supposed to reflect the
there are now numerous available AEDs, the number of patients
concentration and pharmacological action at target in the
that are not responding to a first AED is 50%, and one-third is
brain. The only exception to this is vigabatrin, which is an
still regarded as being treatment resistant, many of which have
irreversible inhibitor of the enzyme responsible for the
several seizure types [10,11]. Indeed, the choice of the appro-
degradation of GABA, GABA transaminase. This can result
priate AED for different seizure types is of paramount

CONTACT Cecilie Johannessen Landmark cecilie.landmark@hioa.no Program for Pharmacy, Oslo Metropolitan University and the National Center for
Epilepsy, Pilestredet 50, N-0167 Oslo/G. F. Henriksens Vei 23, Sandvika, Oslo N-1300, Norway and Deparment of Pharmacology, Oslo University Hospital, Pilestredet
50, N-0167 Oslo/G. F. Henriksens Vei 23, Sandvika, Oslo N-1300, Norway
© 2020 Informa UK Limited, trading as Taylor & Francis Group
2 C. JOHANNESSEN LANDMARK ET AL.
Article highlights
● The pharmacokinetic variability of all AEDs is extensive, resulting in
pronounced variability in serum concentrations between patients,
and may be challenging in special patient groups such as children,
pregnant women, and the elderly
● Therapeutic drug monitoring (TDM) contributes to quality assurance
of the treatment, taking pharmacokinetic variability, drug interac-
tions, adherence, and other treatment challenges into account
● Future advances for TDM of AEDs include use of additional markers of
toxicity and genetic variability to individualize and optimize
treatment
This box summarizes key points contained in the article.
importance, as some AEDs are specifically effective in certain
seizure types, for example, ethosuximide in absence seizures and
stiripentol in Dravet syndrome [12,13]. Thus, in patients with
refractory epilepsy with a challenging treatment and seizure
occurrence, TDM may be a valuable tool to optimize and indivi-
dualize AED treatment and to monitor treatment over time.
The aim of this review is to provide an updated overview of
the current evidence of the use and implementation of TDM in
epilepsy and other indications. Reasons for TDM will be high-
lighted, such as pharmacokinetic variability, drug interactions,
adherence, and other treatment challenges, where TDM con-
tributes to provide a quality assurance of the treatment.
Furthermore, key principles relating to the appropriate inter-
pretation of the reference range and individual reference con-
centrations, matrix selection, and analytical aspects will be
discussed. Overall, we aim at presenting evidence-based
knowledge allowing appropriate and optimal implementation
of TDM in clinical settings.
2. Search strategy and selection criteria
This study is a review based on published articles and searches
in PubMed and Google Scholar, up to January 2020, with
a focus on recent advances from the last 10 years. Peer-
reviewed articles in internationally recognized journals or
scientific books written in English are included, and primary
sources were preferred. The included search terms included
one or more of the following, alone or in combination: anti-
epileptic drugs, and all the individual AEDs: brivaracetam,
carbamazepine, carbamazepine-epoxide, clobazam, clonaze-
pam, diazepam, eslicarbazepine acetate, ethosuximide, felba-
mate, fosphenytoin, gabapentin, lacosamide, lamotrigine,
levetiracetam, oxcarbazepine, perampanel, phenobarbital,
phenytoin, pregabalin, primidone, rufinamide, stiripentol,
sulthiame, tiagabine, topiramate, valproic acid, vigabatrin,
and zonisamide. Other terms included cytochrome P-450,
dried blood spots, drug interactions, epilepsy, pharmacology,
pharmacokinetics, pharmacokinetic variability, pharmacoge-
netics, precision medicine, serum or plasma, and TDM.
3. Pharmacological variability of AEDs
Factors contributing to pharmacological variability within and
between patients are described, such as pharmacokinetic
variability in general and in special patient groups, drug inter-
actions, and pharmacogenetic variability.
3.1. Pharmacokinetic variability in special patient
populations
During the transition from childhood, adolescence, adulthood,
and further to old age, significant changes in physiology and
pathology occur, such as hepatic and renal function, uremia,
and other diseases contributing to changes in the pharmaco-
kinetic characteristics of AEDs [1–6] (see Tables 1 and 2).
3.1.1. Infants and children
In children, physiological alterations cause rapid changes in
pharmacokinetics during early childhood. For most AEDs that
have been studied in the youngest children, the clearance is
high, and thus, the elimination half-life is low, especially from
6 months to about 6 years of age. The volume of distribution
also changes [3,14–16]. The clinical impact is that infants and
young children often need a higher dosage per kilogram body
weight than older children and adolescents. This extensive
pharmacokinetic variability during development makes it dif-
ficult to predict optimal therapeutic doses, and TDM may be
particularly helpful in these patient groups. In older children
and adolescents, the pharmacokinetics are similar to that in
adult populations.
3.1.2. Women during pregnancy
Physiological processes change in pregnancy, and these
changes lead to decreased absorption, altered distribution,
decreased protein binding of highly bound drugs, increased
metabolism due to increased enzyme capacity of cytochrome
P450 (CYP) and uridine glucuronyl transferase (UGT) isoen-
zymes, and increased excretion [2,17,18]. The result is an
increase in serum concentration/dose-ratio from up to 300%
for lamotrigine to 30–50% for other newer AEDs including
levetiracetam, oxcarbazepine, topiramate, and zonisamide,
during pregnancy and with rapid changes back to baseline
post-partum [17–26]. Gabapentin, now most relevant for
women with neuropathic pain, also decreases in serum con-
centrations during pregnancy [27]. The use of valproate is now
contraindicated during pregnancy unless other alternatives
have failed due to increased risk of teratogenic and long-
term cognitive development and autism-spectrum disorders
in the offspring [28–30]. The pharmacokinetic variability of
valproate in women is extensive, and for a safe management
of highly protein-bound drugs like valproate, it might best be
guided by measurement of free, unbound, concentrations
[31,32].
3.1.3. The elderly and patients with hepatic and renal
impairment
The clearance of all AEDs is reduced by 30–50% in the elderly, and
in some cases, even greater changes with up to 90% have been
observed [15]. Pronounced physiologic changes affect the phar-
macokinetic processes in the body and thus characteristics of
AEDs, such as decreased absorption, altered distribution, and
decreased metabolic capacity, blood flow to eliminating organs,
and thus hepatic and renal clearance [3,6]. Polypharmacy is

Table 1. Indications for TDM and clinical consequences.
Indications for TDM
When a drug is initiated, or dosage
or formulation is changed
When an optimal therapeutic
outcome is reached
When adverse effects occur
If nonadherence is suspected
At therapeutic failure
Individual variations between dose
and serum concentrations
Pharmacokinetic variability in special Children, pregnant women, and the
patient populations
Pharmacokinetic interactions
Emergency situations: overdose,
status epilepticus, acute
pathological states (e.g. stroke,
surgery, head trauma)
Clinical consequence and guidance in
further therapy
Determine the serum concentration as
a guide to further follow up and
confirm that the change in serum
concentration is reflected by the
change in dosage. This is of
particular importance for AEDs with
saturation kinetics (phenytoin,
stiripentol) and non-linear kinetics
(carbamazepine, valproic acid,
gabapentin). Following a change of
formulation, Cmax and Tmax may
differ.
Establish an ‘individual therapeutic
concentration’ of the AED as
a guide for future changes in the
therapy
Confirm whether the serum
concentration is high and might be
a probable cause of drug toxicity.
This is of special importance for
drugs with a rapid absorption and
high Cmax values such as
oxcarbazepine or benzodiazepines.
Serial serum concentrations when an
individual reference concentration
has been established may reveal
variable adherence that should be
discussed with the patient
To establish whether a lack of efficacy
may be due to a suboptimal dose/
serum concentration or if the dose/
serum concentration is too high
and may produce a paradoxical
worsening of seizures, or if poor
adherence is suspected
Pharmacokinetic or pharmacogenetic
variability, ethnicity, age,
pharmacoresistance, concurrent
illness, and organ function (liver,
kidneys) are among factors that
contribute to inter-individual
variability and which applies to all
AEDs. Pharmacogenetic variability
may, for instance, be identified by
unexpectedly high ratios between
clobazam and the active metabolite
desmethylclobazam (due to
CYP2C19 polymorphism).
elderly have different dose
requirements due to alteration in
physiology and consequently AED
pharmacokinetics
Pharmacokinetic interactions are
common in epilepsy and result in
increases or decreases in AED
serum concentrations with
potential occurrence of adverse
effects or seizure breakthrough,
respectively. AED interactions
involving non-AEDs are also
prominent.
To guide when the AED dose should
be reinstated to maintain seizure
control. Determine possible
nonadherence and guide a suitable
dosage regimen to control seizures.
Acute changes in pharmacokinetics,
for example in protein binding,
may occur.
EXPERT OPINION ON DRUG METABOLISM & TOXICOLOGY 3
common in the elderly, with up to nine concomitantly prescribed
CNS-active drugs being reported [9]. The elderly may show
increased pharmacodynamic sensitivity to AEDs and other drugs,
and therapeutic and toxic effects may occur at even low concen-
trations. Interpretation of the TDM results should, therefore, be
evaluated more cautiously.
As most AEDs are metabolized by the liver, hepatic disease
may alter clearance [3,6]. Renal function is especially relevant
for AEDs eliminated partly or mainly by renal excretion, such
as pregabalin, gabapentin, levetiracetam, lacosamide, and vig-
abatrin [3,6]. Many AEDs are efficiently removed during dialy-
sis but may be challenging to handle, and TDM may help
guide replacement dosages to maintain seizure control. In
patients with hepatic and renal diseases, TDM is recom-
mended, and for highly bound AEDs, the free, unbound con-
centrations may better guide treatment, as the change in
protein binding and clearance is unpredictable and few stu-
dies have been performed.
3.2. Drug interactions
In epilepsy, monotherapy is preferred, but since one-third of
patients are suffering from refractory epilepsy, polypharmacy
with several AEDs is often necessary. A challenge in the man-
agement of polypharmacy is pharmacokinetic interactions, as
there are numerous interactions between AEDs, where potent
enzyme inducers and inhibitors are among the most com-
monly used AEDs (for review, see [1,4,33–37]).
Pharmacokinetic interactions may be controlled for by the
use of TDM since changes in serum concentrations are
a consequence of changes in metabolism [2–4,6]. When an
interacting drug is withdrawn, the interaction will be reversed,
and thus, it is just as important to adjust for any dosage
changes made accordingly, and this is best guided by TDM.
Enzyme induction leads to decreased serum concentrations
and an increased risk of seizure breakthrough. Enzyme induc-
tion is completed within 2–3 weeks, and therefore, serum
concentration measurements should be performed at this
point. Enzyme inhibition, on the other hand, may give rise to
increased serum concentrations and excessive adverse effects
or toxicity and implies that a new steady-state serum concen-
tration is achieved, depending on the half-life of the affected
drug and takes about five half-lives after the inhibiting drug
has been initiated. The clinical consequence of an interaction
may be difficult to predict in the individual patient due to
other patient-specific features. Thus, TDM may be used to
determine the magnitude of the interactions and make proper
dosage adjustments, with an individual therapeutic concentra-
tion of the patient as a baseline.
Knowledge of the mechanism of interactions helps in decision-
making, as no database is complete or updated at all times. For
instance, valproate, stiripentol, and felbamate are potent enzyme
inhibitors of certain CYPs and UGT enzymes and affect the serum
concentrations of other AEDs [1–6,35–37]. Typical enzyme indu-
cers include carbamazepine, phenytoin, and phenobarbital
(including primidone), acting on several hepatic enzymes, but
4 C. JOHANNESSEN LANDMARK ET AL.

Table 2. Useful pharmacokinetic characteristics of AEDs so as to aid the implementation and interpretation of TDM data.
Time to
peak Time to
conc. steady Half-life, Half-life, Half-life, Protein Route of elimination Reference Reference
Drug (h) state (days) adults (h) children (h) elderly (h) binding (%) (mainly hepatic) range (mg/L) range (μmol/L)
First-generation antiepileptic drugs
Carbamazepine 4–8a 2–4 8–20b 10–13b 30–50b 75 CYP1A2, 2C8, 3A4 4–12 17–51
Clobazam Desmethyl 1–3 2–7 10–30 ~16 30–48 90 CYP3A4 0.03–0.3 0.1–1.0
clobazam (metabolite) 7–10 36–46 2C19 0.02–0.07 1.0–10.5
Clonazepam 1–4 2–10 17–56 22–33 ____ 90 CYP2B, 2E1, 3A4 0.02–0.07 0.06–0.22
Ethosuximide 1–4 8–12 40–60 30–40 ____ 22 CYP2B, 2E1, 3A4 40–100 283–708
Phenobarbital 2–4 15–29 70–140 63–69 ____ 48 CYP2E1, 2C19 10–40 43–172
Phenytoin 1–12 6–21 30–100b 30–100b ____ 92 CYP2C9, 2C19 10–20 40–79
Primidone 2–6 2–4 7–22 5–11 ____ 33 CYP2E1, 2C9/19? 5–10 23–46
d
Valproic acid 3–7 2–4 12–16b 8–13b ____ 74–93d CYP2A6, 2C9/19, 2B6, 50–100 346–693
UGT1A3, 2B7
Second-generation antiepileptic drugs
Felbamate 2–6 3–5 16–22 ____ ____ 48 CYP3A4, 2E1 30–60 126–252
Gabapentin 2–3 1–2 5–9b ____ ____ 0 No, renal 2–20 12–117
Lamotrigine 1–3 3–7 15–35 ____ ____ 66 UGT1A4, 2B7 3–15 10–59
Levetiracetam 1–2 1–2 6–8 5–6 10–11 3 Type B esterase 12–46 70–270
c
Oxcarbazepine 4–6 2–3 8–15 ____ ____ 40 Arylketone reductase, 3–35 12–139
UGTs
Pregabalin 1–2 1–2 5–7 ____ ____ 0 No, renal 2–8 13–50
Tiagabine 0.5–2 1–2 5–9 ____ ____ 98 CYP3A4 0.02–0.2 0.05–0.53c
Topiramate 2–4 4–5 20–30 13–20 ____ 20 CYP3A4 5–20 15–59
Vigabatrin 1–2 1–2 5–8 ____ ____ 17 No, renal 2–36 6–279
Zonisamide 2–5 10–15 50–70 ____ ____ 44 CYP3A4 10–40 47–188
Third-generation antiepileptic drugs
Brivaracetam 0.5–2 2 7–8 ____ ____ 35 Hydrolysis, CYP2C19 0.2–2.0 1–10.0
Eslicarbazepinec 2–3 4–5 20–24 ____ ____ 44 Esterases, UGTs, ? 3–35 12–139
Lacosamide 1–2 2–3 12–16 ____ ____ 14 CYP2C19 10–20 40–80
Perampanel 0.25–2 14 52–129 ____ ____ 98 CYP3A4 0.05–0.4 0.14–1.14
Rufinamide 3–6 1–2 6–10 ____ ____ 28 Hydrolysis, non-CYP 30–40 126–168
dependent
Stiripentol 1–2 7 4–13b ____ ____ 96 CYP1A2, 2C19, 3A4 4–22 17–94
a
Conventional tablets; Nonlinear pharmacokinetics t; cValues refer to pharmacologically active metabolite licarbazepine (10-hydroxycarbazepine); dEnteric-coated
b

tablets. Half-lives are based on monotherapy. N.E. = not established. Based on [2,3,6,11,12].

the latter is weaker as an inducer on CYP3A4 [38]. Carbamazepine 3.3. Pharmacogenetic variability in metabolizing
undergoes autoinduction so that its clearance can increase three- enzymes
fold within several weeks of starting therapy; also, the formation of
Genetic polymorphisms in drug-metabolizing enzymes, such
the active epoxide metabolite varies over time [39,40].
as CYP2C9, CYP2C19, and CYP4CA, also contribute to pharma-
Consequently, it is important to undertake TDM after autoinduc-
cological variability of AEDs. CYP2D6, a common metabolizing
tion has completed.
isoenzyme, is not involved in AED metabolism. These muta-
Lamotrigine is for instance affected by both enzyme inducers
tions may be identified by genotyping [3,51]. Simple kits for
and inhibitors [41,42]. In some cases, pharmacokinetic interactions
CYP genotyping are available as specific CYP kits or as part of
and pharmacogenetic variability in metabolizing enzymes may be
broader biochemical screening kits. This could be useful as
revealed by the measurement of the drug and metabolite, such as
a-priori testing for certain drugs where mutations such as poor
for clobazam and the active metabolite desmethyl-clobazam
metabolizing phenotypes give rise to excessive adverse effects
[43,44]. Drugs that are only renally excreted are not likely to be
at therapeutic doses. Perhaps these kits could be used where
involved in pharmacokinetic interactions, such as gabapentin,
well-equipped TDM laboratories are not established. However,
pregabalin, and vigabatrin.
limitations might still be costs, precision, and evaluation of the
In addition to polypharmacy with AEDs, many patients
results. To assess the pharmacokinetic phenotype in patients,
suffer from comorbid psychiatric affects where additional
probe drug phenotype testing has been investigated for spe-
pharmacological treatment is needed such as antidepressants
cific CYP enzymes where pharmacogenetic variability plays
and antipsychotics and where interactions are likely to occur
a role, such as caffeine for CYP1A2 or omeprazole for
[9,45,46]. Other important disorders require the use of drug
CYP2C19. The value in clinical practice is, however, limited to
classes often involved in interactions, such as analgesics, anti-
the fact that few drugs are metabolized by a single CYP
microbials, antineoplastic agents, HIV drugs, immunosuppres-
isoenzyme only, and conventional TDM seems to be more
sants, cardioactive drugs including warfarin or newer oral
applicable [52].
anticoagulants, and steroids including oral contraceptives
However, in many cases, it is easier to monitor the serum
[36,44–50].
concentration and adjust the dose needed in the particular

patient. Indeed, it has recently been pointed out that, in
clinical practice, genetic testing is only recommended in
a very limited number of cases [53]. Then, additional phar-
macogenetic testing may elucidate the reason for unex-
pected relationships in serum concentrations and dose (C/
D) of certain AEDs where CYP2C9 and 2C19 and, to some
extent, UGTs have polymorphisms, resulting in altered meta-
bolic capacity. Susceptible AEDs where pharmacogenetic
variability is a concern include clobazam, phenytoin, and, to
a lesser extent, lamotrigine [43,44,54]. For valproate, poly-
morphisms in these enzymes did not correlate to significant
changes in C/D-ratios and does therefore not seem to be of
clinical relevance [55].
Pharmacoresistance could be explained by genetic variabil-
ity in the expression of drug transporters such as
P-glycoprotein among other hypotheses but is still under
debate and needs further research [51,56]. An interesting
approach was recently demonstrated by using
a bioinformatic in silico model for predicting dysfunctional
genes such as solute carrier genes and their contribution to
pharmacoresistance in epilepsy [57].
4. Principles for TDM
There are several reasons why it might be difficult to identify
the optimal dose(s) in the individual patient on clinical
grounds alone: (1) clinical effects of AEDs correlate better to
the serum concentration than to the dose due to extensive
pharmacokinetic variability both between and within patients;
(2) the nature of seizures is variable in intensity and intervals;
(3) variable adherence contributes to variable drug exposure;
(4) it might be difficult to recognize signs of toxicity on clinical
grounds; and (5) there are no laboratory markers for clinical
efficacy or toxicity of AEDs [2-6].
4.1. Matrix for measurement: serum/plasma, saliva, and
dried blood spots
For AED TDM, serum or plasma is most commonly used, and
reference ranges are based on measurements of the total
concentration of the drug [2,6,7]. Saliva may also be employed
since concentrations in saliva reflect the pharmacologically
active serum unbound drug concentrations for several AEDs
[8]. Saliva sampling can be undertaken by patients or their
caregivers and may be useful in children and other vulnerable
patients. Sampling is simple and noninvasive, and moreover,
multiple samples may be collected. The sampling conditions
need to be standardized since the saliva concentrations of
AEDs can be affected by contamination of mucus and the
presence of residual drug and food in the mouth [8]. If the
conditions are well controlled, saliva concentrations may be
used to individualize AED treatment. This may be useful when
protein binding is altered for highly protein-bound AEDs [2,6–
8]. Dried blood spot analysis is an alternative technique and is
in increasing use consequent to the recent improvement in
technology and analytical sensitivity [58,59]. It was, however,
highlighted in a recent review that more attention should be
drawn at the clinical validation of such methods [60]. Home-
sampling in vulnerable patients is also possible [61–63]. A new
EXPERT OPINION ON DRUG METABOLISM & TOXICOLOGY 5
micro-sampling tool has also recently been described which
aids ease of use [64,65].
4.2. What to measure? Total/unbound concentrations
and pharmacologically active metabolites
For the majority of patients, the total plasma or serum AED
concentration is measured [4,6]. However, for highly protein-
bound AEDs (>90% bound, e.g. phenytoin and valproic acid
and possibly perampanel, stiripentol, and clobazam), measure-
ment of free, unbound concentrations may be indicated, as
albumin and thus protein binding are decreased, e.g. in the
elderly, those with decreased organ function or during preg-
nancy. The consequence of increased unbound drug concen-
tration is adverse effects even at moderate total
concentrations [7].
Carbamazepine has a pharmacologically active metabolite
(carbamazepine-10,11-epoxide) that is measured in many
laboratories because it is equipotent to carbamazepine and is
commonly associated with adverse effects. The concentration
of the epoxide metabolite is highly variable and is dependent
on age, autoinduction of carbamazepine, and co-medication.
For example, valproate, phenytoin, phenobarbital, and brivara-
cetam increase the concentration of the epoxide and can cause
adverse effects [66–70]. Increased concentrations of the epox-
ide could result in adverse effects. Based on these findings, the
concentration of the epoxide in the blood is referred to be
5–15% of the parent drug [66,67].
Clobazam also has an active metabolite, desmethyl-
clobazam, and its concentration in serum can be 10-fold
higher than the parent drug [43,44]. Experience has shown
that measurement of desmethyl-clobazam can be very useful
as a marker of adverse effects in many patients [6,43,44,71].
4.3. Quality assurance and methodological aspects
For optimal quality assurance, the laboratories offering a TDM
service should be part of an independent quality assurance
program and use evaluated analytical methodologies. Typical
methodologies include HPLC/UPLC combined with UV- or MS/
MS detection and immunological methods. Increasingly, LC-
MS is becoming the methodology of choice. Of course, the use
of such advanced methodologies requires highly qualified
staff with the ability not only to analyze samples but also to
undertake equipment maintenance.
To achieve comparable results from one measurement to
another and between patients, the blood sampling time for
individual patients should be standardized. Trough concentra-
tions are preferred, and it should be noted that the various
reference ranges comprise trough concentrations [3–6,71]. It is
recommended that blood samples are drawn at steady state,
and typically, this entails about five half-lives after initiating
treatment or following a dose adjustment. For all AEDs, the
ideal sampling time is in the morning, before intake of the
morning dose, representing the trough concentration. For
outpatients, the morning dose can be postponed for
a couple of hours to obtain this. In the case of toxic symptoms,
another sample may be drawn at the time when adverse
effects occur to determine whether the symptoms are indeed
6 C. JOHANNESSEN LANDMARK ET AL.
drug related. Recently, postictal TDM has been shown to be
useful after unexpected breakthrough seizures so as to assess
adherence [72,73].
4.4. Cost-effectiveness
Few studies have been performed to assess the cost-
effectiveness of the use of AED TDM, and indeed, an
overview of the cost-effectiveness of TDM for various
other therapeutic classes reports the same lack of studies
[74]. Eadie reviewed 25 years of practice following the
introduction of AED TDM and found a significantly higher
rate of seizure freedom in those who had access to TDM
during the first 6 months after their first seizure [75].
Furthermore, he discussed the possible cost-effectiveness
regarding a decreased need for drug dosage in some
patients and the lack of extra costs related to the devel-
opment of adverse effects [76]. Such studies are still lack-
ing to support these assumptions in terms of reduction in
costs, hospitalization, or other outcome measures. Two
studies have been performed, where groups could be
divided to access to TDM or not, in India and Iraq
[77,78]. In the study from India, 25 patients who had
been monitored with TDM and 25 without, and
a retrospective pharmacoeconomic analysis was performed
after 1 year. The outcome measures demonstrated signifi-
cant improvement in seizure control, remission, adverse
effects, and quality of life measures. The direct costs
included cost to the hospital of providing the TDM service
and savings in cost for the hospital and patient
per seizure saved. The cost for two TDM samples
per year was 60 Indian rupees, and the saving in terms
of obtained seizure control was significant, even though it
is difficult to extract the direct savings from the results
[77]. The study from Iraq included 132 children from 2
years of age with structural metabolic epileps and inves-
tigated the cost-effectiveness of the use of TDM retro-
spectively, according to follow-up with or without TDM.
Effectiveness was defined as >50% seizure control or sei-
zure freedom. TDM was found cost-effective in terms of
Figure 1. Pharmacological variability between patients and use of therapeutic drug monitoring (TDM). The figure illustrates the steps from prescription of an
antiepileptic drug to appropriate use and monitoring of serum concentrations, taking patient-specific features into account, such as adherence, pharmacokinetic,
pharmacodynamic, and pharmacogenetic variability.
a 7% reduction in costs for those with >50% seizure free-
dom and a 22% reduction in costs following a 3-month
seizure-free period. The incremental cost-effectiveness
ratio was sensitive to the cost of management. The
authors call for longer follow-up periods in future studies
[78]. In a recently published study, the economical burden
for caregivers was highlighted based on a questionnaire to
500 caregivers for persons with epilepsy in the US. It was
demonstrated that the burden was nearly 48 billion USD
per year and greatest for those who care for children with
frequent seizures. Thus, the impact on caregivers also
should be considered when estimating the values of inter-
ventions to control epilepsy [79].
5. Implementation of TDM – current status
TDM provides bespoke AED treatment of patients with epilepsy.
Table 1 highlights the indications for AED TDM, while Table 2 lists
the various useful pharmacokinetic characteristics of AEDs so as
to aid the implementation and interpretation of TDM data.
Figure 1 is a schematic of variables that need to be considered
when TDM is undertaken. The ultimate goal is to determine the
patient’s individual AED therapeutic concentration and range,
and this approach is useful for all AEDs.
5.1. How to use the terminology of reference ranges and
individual therapeutic concentrations
In 2008, the International League Against Epilepsy provided
guidelines as to how to use the terminology of reference
ranges and the individual therapeutic concentrations [6].
5.1.1. Reference ranges
Two separate terms are recommended to define a drug con-
centration range in relation to clinical efficacy. The ‘reference
range’ is the range of drug concentrations quoted by the
laboratory and specifies a lower limit, below which
a therapeutic response is relatively unlikely to occur and an
upper limit above which toxicity is likely to occur [2,6,80]. The
range is therefore not a ‘therapeutic range,’ which is

associated with the best response in all patients. The thera-
peutic range varies between different patients and can only be
determined for the individual patient. Therefore, it is recom-
mended to use the term ‘individual therapeutic concentration’
[2,6,80].
It should be emphasized that because of large inter-
individual differences in the type of epilepsy and severity of
seizures, the effective AED concentration can vary significantly
from patient to patient. Thus, patients can readily achieve
therapeutic benefit at serum concentrations outside these
ranges. Furthermore, it is not unusual for some patients to
have optimum seizure control at serum concentrations below
the lower value of the reference range, while others may
require drug concentrations above the upper limit of the
reference range. Therefore, while the initial treatment goal is
to adjust drug dosages to achieve serum concentrations
within the reference range, it should be emphasized that it is
important to treat the single patient and not the blood con-
centration [81]. It is thus inappropriate to adjust the dosage to
achieve blood concentrations within the reference range with-
out taking into consideration the clinical status of the patient,
which is inappropriate.
For many years, reference ranges have been quoted for
the first-generation AEDs (as carbamazepine, ethosuximide,
phenytoin, phenobarbital, and valproic acid) [82–84].
Presently, reference ranges are quoted for all the second-
and third-generation AEDs [3,6,66–70]. However, because of
the considerable individual variability, the value of the
lower limit of the therapeutic range has been questioned.
Recently, a national approach to harmonize and update AED
reference ranges between laboratories so as to improve
quality assurance and enhance patient management coun-
try-wide was published by Reimers et al. [71].
5.1.2. Individual therapeutic concentrations
By employing the concept of ‘individual therapeutic concen-
trations,’ where intra-individual comparisons of serum concen-
trations over time are used, TDM can be helpful for all AEDs
[6,80]. When an optimal effect of a drug is achieved, the
corresponding serum concentration will then serve as the
individual reference for comparison if future treatment
changes occur or there is a change in the clinical status of
the patient. It is important to keep in mind that the basis for
the application of TDM relies on a relationship between drug
serum concentration and clinical effect in the individual
patient. The optimal treatment may be best guided by identi-
fying the ‘individual therapeutic concentration’ since the phar-
macokinetic variability between patients is extensive for all
AEDs [2–6,80].
5.2. Indications for therapeutic drug monitoring of AEDs
The older, first-generation AEDs (carbamazepine, phenytoin,
phenobarbital, primidone, and valproic acid) exhibit exten-
sive interpatient pharmacokinetic variability and also satura-
tion kinetics for phenytoin, and therefore, TDM has been
applied for these drugs for more than 50 years [4]. TDM is
also increasingly being used to optimize treatment with the
various new second-generation AEDs, such as lamotrigine,
EXPERT OPINION ON DRUG METABOLISM & TOXICOLOGY 7
gabapentin, pregabalin, levetiracetam, oxcarbazepine, topir-
amate, and zonisamide. Emerging evidence also shows the
usefulness of TDM for the third-generation AEDs such as
brivaracetam, lacosamide, eslicarbazepine, and perampanel
and the orphan drugs, stiripentol and rufinamide. For all
AEDs, the indications for monitoring are the same and are
presented in Table 2 [2,3,71,85–95].
5.2.1. Other non-epilepsy comorbidities
AEDs are also increasingly used to treat non-epilepsy comor-
bidities. These include, for example, gabapentin and pregaba-
lin for the management of neuropathic pain and lamotrigine,
valproate, and carbamazepine for the management of various
psychiatric conditions [92,93]. Although these AEDs show the
same pharmacokinetic characteristics, they are rarely moni-
tored. Interestingly, a 22-fold variability in gabapentin C/
D-ratios in a series of 120 patients with restless legs syndrome
has been reported [94]. Increasingly, TDM is used to guide
antidepressant and antipsychotic treatment, and consensus
guidelines for TDM in neuropsychopharmacology from the
German TDM task force are in place [52]. It is noteworthy
that the reference ranges for the AEDs used in psychotherapy
(e.g. lamotrigine, valproate, and carbamazepine) are exactly
the same as those used to treat epilepsy [52,96].
5.2.2. Adherence
Poor or variable adherence is a major clinical challenge and is
the principal factor that contributes to variability in serum
concentrations between patients. Nonadherence is a major
problem in the treatment of epilepsy as it compromises sei-
zure control. The World Health Organization states that the
use of TDM is the best way to identify and control for poor
adherence [97].
In children and adults with epilepsy, nonadherence has
been shown to be 30–40% [61,98–104]. Subtherapeutic con-
centrations, below the reference range, can also be explained
by an inadequate low dose or by hepatic enzyme induction,
and TDM is useful to differentiate between these, particularly
if an individual reference concentration has been obtained
[103]. In a study comprising 50 patients with refractory epi-
lepsy, 40% of patients were identified as being nonadherent,
as measured by >30% change in serum concentration as
compared to their individual reference concentrations. Of
these patients, 66% were consuming higher doses, whereas
22% of patients consumed lower doses than prescribed (11%
undefined) [102].
A more recent study of 99 patients in a tertiary center reported
a lower 20% incidence of nonadherence, and this can be
explained by the fact that drug ingestion is probably better
supervised [101]. In patients admitted to hospital due to acute
seizures, serum concentrations in 40% of patients were below
50% of their baseline steady-state concentrations [73], and 40%
of those patients with low serum concentrations denied poor
adherence. These data highlight that forgetting to take AEDs
regularly has important clinical implications and should be dis-
cussed with patients so that to enhance their understanding of
the problem and its consequence [104]. In a large Internet-based
questionnaire, it was identified that 40% of patients admitted to
forgetting drug intake sometimes/often, while 30% admitted
8 C. JOHANNESSEN LANDMARK ET AL.
that they intentionally took their AEDs differently than agreed
upon with their treating physician [79]. Another study was based
on questionnaires given to 175 patients and their neurologists
and showed that, in one-third of the cases, patients and their
treating neurologist did not agree upon the given AED(s) or AED
dosing [105]. Intentional poor adherence could be due to adverse
effects, concerns about polypharmacy, suitability of intake, taste
of tablets, etc. AED generic substitution is an emotional issue
whereby patients are reluctant to ingest generics because they
can be of different color or shape. Generics are considered bioe-
quivalent to brand formulations, and TDM can be useful in iden-
tifying whether any adverse effects or enhanced seizers are drug
related [106]. There is a need for improvement in communication
between patients and health-care professionals to improve the
quality of the AED treatment.
5.3. Interpretation of results and impact of TDM on
clinical outcome
TDM is a useful tool for guiding the clinical management of
patients with epilepsy. However, it is only useful if there is an
appropriate indication that blood sampling is correctly underta-
ken and the analytical request forms are completed with the
required clinical and sample information. Increasingly, a multi-
professional team comprising epileptologist, or other physician,
a pharmacist, a clinical pharmacologist, and an epilepsy practice
nurse is in place and can result in a robust effort to provide optimal
patient care. While the reference range is useful in the first
instance to guide treatment, it is important that the individual
therapeutic concentration is identified as quickly as possible.
6. Conclusion
Table 1 highlights the principal indications for AED TDM,
while Table 2 highlights the useful pharmacokinetic characteris-
tics that are needed so as to aid implementation and interpreta-
tion of TDM data. Because TDM provides a pragmatic approach
to epilepsy care with AEDs, AEDs are among the most common
medications for which TDM is undertaken. Indeed, AED TDM
enables bespoke dose adjustments based on actual drug con-
centration measurements so as to optimize treatment outcome.
It is important to understand the concept of the reference range
because for the majority of patients, if their serum concentrations
are within these ranges, they will exhibit optimum clinical
response. Some patients, however, may require concentrations
outside the reference ranges consequent to individual variation
in seizure severity and seizure type. Equally, it is important to
understand and to apply the concept of the ‘individual thera-
peutic concentration’ which is specific for an individual patient
and reflects his/her optimum treatment regimen.
Serum or plasma is the matrix of choice for AED TDM.
However, with the introduction of sensitive analytical instru-
mentation, many AEDs can be readily monitored in saliva or
dried blood spots. Increasingly a multi-professional team com-
prising epileptologist, or other physician, a pharmacist,
a clinical pharmacologist, and an epilepsy practice nurse is in
place to interpret TDM data, and this can result in a robust
effort to provide optimal patient care.
7. Expert opinion – future prospects
7.1. Expert opinion on TDM of AEDs
Advances in further research and application of TDM in various
clinical settings are promising. AED TDM is a well-established
tool for the management of patients with epilepsy. Patient-
specific factors contribute to extensive pharmacokinetic varia-
bility that may be accounted for to individualize the treatment.
In refractory epilepsy, a long-term TDM approach may help to
solve challenges such as unsatisfactory seizure control, frequent
changes in therapy, nonadherence, polypharmacy aspects, and
excluding pseudo-resistance due to sub-optimal use of AEDs
[73,100,104,107,108]. Also, when new treatments become avail-
able, pharmacokinetic challenges are evolving, and TDM is
a useful tool. Recent treatment options include everolimus
(tuberous sclerosis), cannabidiol (Dravet and Lennox Gastaut
syndrome), and fenfluramine (Dravet syndrome) [109]. New
areas for AED TDM include other indications, such as lamotri-
gine in psychiatric indications and gabapentin and pregabalin
in neuropathic pain [4,9,94]. The clinical outcome may be diffi-
cult to assess also in other indications, and pharmacokinetic
variability within and among the patients is the same regardless
of indication. Ideally, the usefulness of TDM in optimizing AED
treatment in patients with epilepsy is best ascertained by the
use of randomized controlled trial (RCT) design, and a recent
Cochrane review reported that they are sparse and very much
needed [110]. Indeed, there are two previous RCTs comparing
treatment outcome guided with the use of TDM [111,112].
These studies were not able to provide sufficient evidence for
the usefulness of routine monitoring of AEDs in the general
epilepsy population. This does not argue against the value of
TDM in special situations and clinical indications. The nature of
RCTs to study the usefulness of TDM is not possible because
patient-related factors and use of TDM on clinical grounds
make blinding and randomization difficult. An unsuccessful
example of this is a recent prospective RCT during pregnancy
with or without TDM. No difference between the groups on
seizure control or outcome in pregnant women could be
demonstrated due to several limiting factors [113].
7.2. Future prospects of precision medicine in epilepsy
Precision medicine entails tailored or personalized treatment.
Going forward, we can expect new and improved analytical
procedures that will enable a more sensitive analysis to be
performed so that low concentrations of drugs and metabo-
lites can be more readily measured and more rapid and accu-
rate results to be made available quickly. Genotyping of CYP
isoenzymes such as CYP2C9 and 2C19, and UGT isoenzymes, is
likely to become available for a specific use. These tests may
allow avoidance of overdosing due to reduced activity of
metabolic pathways, and thus, patient optimum treatment
will be achieved earlier. Pharmacogenomic approaches
include screening of all gene variants and thus reveal more
causes of e.g. pharmacoresistance [56]. An example is the
identification of SCN1A mutations in Dravet syndrome,
where the voltage-gated sodium channel has a loss of func-
tion. Thus, the introduction of drugs that work via an action on

SVN1A would be ineffective and consequently may worsen
seizures and inadvertently result in refractory epilepsy.
As a supplement to TDM as part of precision medicine,
measurement of more pharmacogenetic and biochemical mar-
kers of toxicity may lead the way forward to avoid toxicity at
early stages in the treatment. The best example is the HLA-
1502 mutations, frequently occurring in South-East Asians, and
with increased risk of Stevens–Johnson syndrome consequent
to carbamazepine and phenytoin treatment. In clinical prac-
tice, pharmacogenetic markers of both HLA and CYP muta-
tions could be tested as a panel to assess risk factors [114–
116]. Another new approach is to use an endogenous biomar-
ker, 4β-hydroxycholesterol, for CYP3A-activity to evaluate the
potency of enzyme-inducing capacity [38]. Another approach
that will possibly be applied and developed in the years to
come is to use population pharmacokinetic modeling so as to
aim at an initial target dosage regime, which can subsequently
be followed by TDM in the individual patient [2]. Such model-
ing allows for dosage adjustments to be undertaken before
reaching steady state and before the measurement of serum
concentrations. This could help clinicians to more rapidly
establish an effective dose. Also, such software includes algo-
rithms so as to allow the determination of pharmacokinetic
variability, drug interactions, and pharmacogenetic factors to
provide a patient-oriented service [2].
Funding
This paper was not funded.
Declaration of interest
The authors have no relevant affiliations or financial involvement with any
organization or entity with a financial interest in or financial conflict with
the subject matter or materials discussed in the manuscript. This includes
employment, consultancies, honoraria, stock ownership or options, expert
testimony, grants or patents received or pending, or royalties.
Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial or other
relationships to disclose.
References
Papers of special note have been highlighted as either of interest (•) or of
considerable interest (••) to readers.
1. Patsalos PN, St Louis EK. The epilepsy prescriber’s guide to anti-
epileptic drugs. 3rd ed. Cambridge: Cambridge University Press;
2018.
2. Patsalos PN, Spencer EP, Berry DJ. Therapeutic drug monitoring of
antiepileptic drugs in epilepsy: a 2018 update. Ther Drug Monit.
2018;40(5):526–548.
• The most recent update on TDM in epilepsy with details on the
various drugs.
3. Johannessen Landmark C, Johannessen SI, Tomson T. Host factors
affecting antiepileptic drug delivery – pharmacokinetic variability.
Adv Drug Deliv Rev. 2012a;64:896–910.
• Thorough update on pharmacokinetic variability of AEDs.
4. Johannessen Landmark C, Johannessen SI, Tomson T. Dosing stra-
tegies of antiepileptic drugs – from one dose to individualisation of
EXPERT OPINION ON DRUG METABOLISM & TOXICOLOGY 9
treatment by implementation of therapeutic drug monitoring.
Epileptic Disord. 2016;18(4):367–383.
5. Johannessen SI, Battino D, Berry DJ, et al. Therapeutic drug mon-
itoring of the newer antiepileptic drugs. Ther Drug Monit.
2003;25:347–363.
6. Patsalos PN, Berry DJ, Bourgeois BF, et al. Antiepileptic drugs – best practice
guidelines for therapeutic drug monitoring: a position paper by the sub-
commission on therapeutic drug monitoring, ILAE commission on therapeu-
tic strategies. Epilepsia. 2008;49:1239–1276.
•• International guidelines for AED TDM.
7. Patsalos PN, Zugman M, Lake C, et al. Serum protein binding of 25
antiepileptic drugs in a routine clinical setting: a comparison of free
non-protein-bound concentrations. Epilepsia. 2017;58
(7):1234–1243.
•• The only study describing details on protein binding in
a clinical setting, which will be important for further analytical
progress and precise measurements of the pharmacologically
active component of many AEDs.
8. Patsalos PN, Berry DJ. Therapeutic drug monitoring of antiepi-
leptic drugs by use of saliva. Ther Drug Monit. 2013;35:4–29.
9. Baftiu A, Feet SA, Larsson PG, et al. Utilization of antiepileptic drugs
in the elderly vs younger patients with epilepsy and psychiatric
comorbidity. Epilepsy Res. 2018;139:35–42.
10. Chen Z, Brodie MJ, Liew D, et al. Treatment outcomes with newly
diagnosed epilepsy treated with established and new antiepileptic
drugs: a 30-year longitudinal cohort study. JAMA Neurol. 2018;75
(3):279–286.
•• Large longitudinal study confirming that one-third of patients
continue to be refractory to AED treatment.
11. Kwan P, Brodie MJ. Early identification of refractory epilepsy. N Engl
J Med. 2000;342:314–319.
•• One of the main references to demonstrate that one-third of
patients are treatment resistant, reconfirmed by Chen et al.,
2018.
12. Glauser T, Ben-Menachem E, Bourgeois B, et al. Updated ILAE
evidence review of antiepileptic drug efficacy and effectiveness
as initial monotherapy for epileptic seizures and syndromes.
Epilepsia. 2013;54(3):551–563.
13. Nunes VD, Sawyer L, Neilson J, et al. Diagnosis and management of
the epilepsies in adults and children: summary of updated NICE
guidance. BMJ. 2012;26:e344:281.
14. Hadjiloizou SM, Bourgeois BF. Antiepileptic drug treatment in
children. Expert Rev Neurother. 2007;7:179–193.
15. Italiano D, Perucca E. Clinical pharmacokinetics of new-generation
antiepileptic drugs at the extremes of age: an update. Clin
Pharmacokinet. 2013;8:627–645.
16. Verotti A, Iapadre G, Di Donato G, et al. Pharmacokinetic considera-
tions for anti-epileptic drugs in children. Exp Opin Drug Metab
Toxicol. 2019;15(3):199–211.
17. Tomson T, Landmark CJ, Battino D. Antiepileptic drug treatment in
pregnancy: changes in drug disposition and their clinical
implications. Epilepsia. 2013;54:405–414.
18. Patel SI, Pennell PB. Management of epilepsy during pregnancy: an
update. Ther Adv Neurol Disord. 2016;9(2):118–129.
19. Tomson T, Battino D. Pharmacokinetics and therapeutic drug mon-
itoring of newer antiepileptic drugs during pregnancy and the
puerperium. Clin Pharmacokinet. 2007a;46:209–219.
20. Petrenaite V, Sabers A, Hansen-Schwartz J. Individual changes in
lamotrigine plasma concentrations during pregnancy. Epilepsy Res.
2005;65:185–188.
21. Pennell PB, Peng L, Newport DJ, et al. Lamotrigine in pregnancy.
Clearance, therapeutic drug monitoring, and seizure frequency.
Neurology. 2008;70:2130–2136.
22. Tomson T, Palm R, Källén K, et al. Pharmacokinetics of levetirace-
tam during pregnancy, delivery, in the neonatal period, and
lactation. Epilepsia. 2007b;48:1111–1116.
23. Mazzucchelli I, Onat FY, Özkara C, et al. Changes in the disposition
of oxcarbazepine and its metabolites during pregnancy and the
puerperium. Epilepsia. 2006;47(3):504–509.
10 C. JOHANNESSEN LANDMARK ET AL.
24. Öhman I, Vitols S, Luef G, et al. Topiramate kinetics during delivery,
in the neonatal period, and lactation: preliminary observations.
Epilepsia. 2002;43:1157–1160.
25. Westin AA, Nakken KO, Johannessen SI, et al. Serum concentration/
dose ratio of topiramate during pregnancy. Epilepsia.
2009;50:480–485.
26. Reimers A, Helde G, Becser Andersen N, et al. Zonisamide serum
concentrations during pregnancy. Epilepsy Res. 2018a;144:25–29.
27. Öhman I, Vitols S, Tomson T. Pharmacokinetics of gabapentin
during delivery, in the neonatal period, and lactation: does a fetal
accumulation occur during pregnancy? Epilepsia.
2005;46:1621–1624.
28. Gerard EE, Meador KJ. An update on maternal use of antiepileptic
medications in pregnancy and neurodevelopment outcomes.
J Pediatr Genet. 2015;4(2):94–110.
29. EMA. Visited March 28th, 2019. https://www.ema.europa.eu/en/
medicines/human/referrals/valproate-related-substances.
30. Tomson T, Battino D, Bonizzoni E, et al. Comparative risk of major
congenital malformations with eight different antiepileptic drugs:
a prospective cohort study of the EURAP registry. Lancet Neurol.
2018;17(6):530–538.
•• Results from a large international registry on pregnancy
outcomes.
31. Johannessen Landmark C, Burns ML, Baftiu A, et al.
Pharmacokinetic variability of valproate in women of
childbearing. Epilepsia. 2017;58(10):e142–e146.
32. Johannessen Landmark C, Farmen AH, Burns ML, et al.
Pharmacokinetic variability of valproate during pregnancy – implica-
tions for the use of therapeutic drug monitoring. Epilepsy Res.
2018;141:31–37.
33. Johannessen SI, Johannessen Landmark C. Antiepileptic drug interac-
tions – basic principles and clinical implications. Curr Neuropharm.
2010;8:254–267.
34. Johannessen Landmark C, Patsalos PN. Drug interactions involving
the new second- and third-generation antiepileptic drugs. Expert
Rev Neurother. 2010;10:119–140.
35. Patsalos PN. Drug interactions with the newer antiepileptic drugs
(AEDs)-part 1: pharmacokinetic and pharmacodynamic interactions
between AEDs. Clin Pharmacokinet. 2013a;52:927–966.
36. Patsalos PN. Drug interactions with the newer antiepileptic drugs
(AEDs)-part 2: pharmacokinetic and pharmacodynamic interactions
between AEDs and drugs used to treat non-epilepsy disorders. Clin
Pharmacokinet. 2013b;52:1045–1061.
37. Patsalos PN. Antiepileptic drug interactions: a clinical guide. 3rd ed.
Switzerland: Springer; 2016.
•• A useful and concise guide that describes all known interac-
tions involving AEDs.
38. Hole K, Wollmann BM, Nguyen C, et al. Comparison of CYP3A4-
inducing capacity of enzyme-inducing antiepileptic drugs using
4β-hydroxycholesterol as biomarker. Ther Drug Monit. 2018;40
(4):463–468.
• New approach to estimate the enzyme-inducing potency of
inducing AEDs.
39. Bertilsson L, Höjer B, Tybring G, et al. Autoinduction of carbamaze-
pine metabolism in children examined by a stable isotope
technique. Clin Pharmacol Ther. 1980;27:83–88.
40. Kudriakova TB, Sirota LA, Rozova GI, et al. Autoinduction and
steady-state pharmacokinetics of carbamazepine and its major
metabolites. Br J Clin Pharmacol. 1992;33:611–615.
41. Johannessen Landmark C, Baftiu A, Tysse I, et al. Pharmacokinetic
variability of four newer antiepileptic drugs, lamotrigine, levetira-
cetam, oxcarbazepine and topiramate-a comparison of the impact
of age and comedication. Ther Drug Monit. 2012b;34(4):440–445.
42. Koristkova B, Grundmann M, Brozmanova H, et al. Lamotrigine
drug interactions in combination therapy and the influence of
therapeutic drug monitoring on clinical outcomes in paediatric
patients. Basic Clin Pharmacol Toxicol. 2019;125(1):26–33.
43. De Leon J, Spina E, Diaz FJ. Clobazam therapeutic drug monitoring:
a comprehensive review of the literature with proposals to improve
future studies. Ther Drug Monit. 2013;35(1):30–47.
44. Burns ML, Baftiu A, Opdal MS, et al. Therapeutic drug monitoring of
clobazam and its metabolite-Impact of age and comedication on
pharmacokinetic variability. Ther Drug Monit. 2016;38(3):350–357.
45. Karouni M, Henning O, Larsson PG, et al. Psychiatric comorbidity in
patients with refractory epilepsy. Epi Behav. 2013;29:77–81.
46. Spina E, Pisani F, de Leon J. Clinically significant pharmacokinetic
drug interactions of antiepileptic drugs with new antidepressants
and new antipsychotics. Pharmacol Res. 2016;106:72–86.
47. Asconapé JJ. Pharmacokinetic considerations with the use of anti-
epileptic drugs in patients with HIV and organ transplants. Curr
Neurol Neurosci Rep. 2018;18:89.
48. Sabers A, Öhman I, Christensen J, et al. Oral contraceptives reduce
lamotrigine plasma levels. Neurology. 2003;61:570–571.
49. Reimers A, Helde G, Brodtkorb E. Ethinyl estradiol, not progestogens,
reduces lamotrigine serum concentrations. Epilepsia.
2005;46:1414–1417.
50. Galgani A, Palleria C, Iannone LF, et al. Pharmacokinetic interac-
tions of clinical interest between direct oral anticoagulants and
antiepileptic drugs. Front Neurol. 2018;9:1067.
51. Löscher W, Klotz U, Zimprich F, et al. The clinical impact of pharma-
cogenetics on the treatment of epilepsy. Epilepsia. 2009;50(1):1–23.
52. Hiemke C, Bergemann N, Clement HW, et al. Consensus guidelines
for therapeutic drug monitoring in neuropsychopharmacology:
update 2017. Pharmacopsychiatry. 2018;51:9–62.
53. Bozina N, Sporis IS, Bozina T, et al. Pharmacogenomics and the
treatment of epilepsy: what do we know?. Pharmacogenomics.
2019;20(15):1093–1101.
• Recent update on the role of pharmacogenomics in epilepsy.
54. Smith RL, Haslemo T, Refsum H, et al. Impact of age, gender and
CYP2C9/2C19 genotypes on dose-adjusted steady-state serum con-
centrations of valproic acid – a large-scale study based on natur-
alistic therapeutic drug monitoring data. Eur J Clin Pharmacol.
2016;72(9):1099–1104.
55. Smith RL, Haslemo T, Chan HF, et al. Clinically relevant effect of
UGT1A4*3 on lamotrigine serum concentration is restricted to
postmenopausal women – a study matching therapeutic drug
monitoring and genotype data from 534 patients. Ther Drug
Monit. 2018;40(5):567–571.
56. Tang F, Hartz AMS, Bauer B. Drug-resistant epilepsy: multiple
hypotheses, few answers. Front Neurol. 2017;8:301. eCollection
2017.
• Recent update discussing various hypothesis for drug
resistance.
57. Mirza N, Vaseiva O, Appleton R. An integrative in silico system for
predicting dysregulated genes in the human epileptic focus: appli-
cation to SLC transporters. Epilepsia. 2016;57:1467–1474.
58. Franco V, Baruffi K, Fransesca Crema TM, et al. Determination of
perampanel in dried blood spots; applicability to therapeutic
drug monitoring. Ther Drug Monit. 2019 Jul 29. Epub ahead of
print.
59. Velghe S, Deprez S, Stove CP. Fully automated therapeutic drug
monitoring of antiepileptic drugs making use of dried blood spots.
J Chromatogr A. 2019;1601:95–103.
60. Wilhelm AJ, den Burger JC, Swart EL. Therapeutic drug monitoring
by dried blood spot: progress to date and future directions. Clin
Pharmacokinet. 2014;53(11):961–973.
61. Shah NM, Hawwa AF, Millership JS, et al. Adherence to antiepileptic
medicines in children: a multiple-methods assessment involving
dried blood spot sampling. Epilepsia. 2013;54:1020–1027.
62. Linder C, Neideman M, Wide K, et al. Dried blood spot
self-sampling by guardians of children with epilepsy is feasible;
comparison with plasma for multiple antiepileptic drugs. Ther
Drug Monit. 2019;41(4):509–518.
63. Linder C, Wide K, Walander M, et al. Comparison between dried
blood spot and plasma sampling for therapeutic drug monitoring
of antiepileptic drugs in children with epilepsy: a step towards
home sampling. Clin Biochem. 2017;50(7–8):418–424.
64. D’Urso A, Cangemi G, Barco S, et al. LC-MS/MS-based quantification
of 9 antiepileptic drugs from a dried sample spot device. Ther Drug
Monit. 2019;41(3):331–339.

65. D’Urso A, Rudge J, Patsalos PN, et al. Volumetric absorptive micro-
sampling: a new sampling tool. Ther Drug Monit. 2019;41
(5):681–692.
66. Johannessen SI, Gerna M, Bakke J, et al. CSF concentrations and
serum protein binding of carbamazepine and
carbamazepine-10,11-epoxide in epileptic patients. Br J Clin
Pharmacol. 1976;3:575–582.
67. Bertilsson L, Tomson T. Clinical pharmacokinetics and pharmacolo-
gical effects of carbamazepine and carbamazepine-10,11-epoxide.
An Update Clin Pharmacokinet. 1986;11:177–198.
68. Pisani F, Caputo M, Fazio A, et al. Interaction of carbamazepine-10-
11-epoxide, an active metabolite of carbamazepine, with valproate:
a pharmacokinetic study. Epilepsia. 1990;31:339–342.
69. Burianová I, Borecka K. Routine therapeutic monitoring of the
active metabolite of carbamazepine: is it really necessary? Clin
Biochem. 2015;48:866–869.
70. Stockis A, Sargentini-Maier ML, Brodie MJ. Pharmacokinetic inter-
action of brivaracetam on carbamazepine in adult patients with
epilepsy, with and without valproate co-administration. Epilepsy
Res. 2016;128:163–168.
71. Reimers A, Andsnes Berg J, Larsen Burns M, et al. Reference ranges
for antiepileptic drugs revisited: a practical approach to establish
national guidelines. Drug Des Devel Ther. 2018b;12:271–280.
72. Specht U, Elsner H, May TW, et al. Postictal serum levels of anti-
epileptic drugs for detection of noncompliance. Epilepsy Behav.
2003;4(5):487–495.
73. Samsonsen C, Reimers A, Bråthen G, et al. Nonadherence to treat-
ment causing acute hospitalizations in people with epilepsy: an
observational, prospective study. Epilepsia. 2014;55(11):e125–128.
• Prospective study to identify poor adherence by using TDM.
74. Touw DJ, Neef C, Thomson AH, et al. Cost-effectiveness of thera-
peutic drug monitoring: a systematic review. Ther Drug Monit.
2005;27:10–17.
75. Eadie MJ. Plasma antiepileptic drug monitoring in a neurological
practice: a 25-year experience. Ther Drug Monit. 1994;16:458–468.
76. Eadie MJ. The role of therapeutic drug monitoring in improving the
cost effectiveness of anticonvulsant therapy. Clin Pharmacokinet.
1995;29:29–35.
77. Rane CT, Dalvi SS, Gogtay NJ, et al. A pharmacoeconomic analysis
of the impact of therapeutic drug monitoring in adult patients with
generalized tonic-clonic epilepsy. Br J Clin Pharmacol.
2001;52:193–195.
78. Salih MR, Bahari MB, Shafie AA, et al. Cost-effectiveness analysis
for the use of serum antiepileptic drug level monitoring in chil-
dren with structural-metabolic epilepsy. Epilepsy Res.
2013;104:151–157.
79. Hussain SA, Ortendahl JD, Bentley TGK, et al. The economical
burden of caregiving in epilepsy: an estimate based on
a survey of US caregivers. Epilepsia. 2020 Jan 17. Epub ahead
of print.
80. Perucca E. Is there a role for therapeutic drug monitoring of new
anticonvulsants? Clin Pharmacokinet. 2000;38:191–204.
• First paper to propose the concept of individual therapeutic
concentrations.
81. Woo E, Chan YM, Yu YL, et al. If a well-stabilized epileptic patient
has a subtherapeutic antiepileptic drug level, should the dose be
increased? A randomized prospective study. Epilepsia.
1988;29:129–139.
82. Buchthal F, Svensmark O, Schiller PJ. Clinical and electroencephalo-
graphic correlations with serum levels of diphenylhydantoin. Arch
Neurol. 1960;2:624–630.
83. Schmidt D, Haenel F. Therapeutic plasma levels of phenytoin,
phenobarbital, and carbamazepine: individual variation in relation
to seizure frequency and type. Neurology. 1984;34:1252–1255.
84. Schmidt D, Einicke I, Haenel FT. The influence of seizure type on
the efficacy of plasma concentrations of phenytoin, phenobarbital,
and carbamazepine. Arch Neurol. 1986;43:263–265.
85. Gidal BE, Ferry J, Majid O, et al. Concentration-effect relationships
with perampanel in patients with pharmacoresistant partial-onset
seizures. Epilepsia. 2013;54:1490–1497.
EXPERT OPINION ON DRUG METABOLISM & TOXICOLOGY 11
86. Svendsen T, Brodtkorb E, Reimers A, et al. Pharmacokinetic
variability, efficacy and tolerability of eslicarbazepine acetate –
a national approach to the evaluation of therapeutic drug mon-
itoring data and clinical outcome. Epilepsy Res.
2017a;129:125–131.
87. Svendsen T, Brodtkorb E, Baftiu A, et al. Therapeutic drug monitor-
ing of lacosamide in Norway: focus on pharmacokinetic variability,
efficacy and tolerability. Neurochem Res. 2017b;42(7):2077–2083.
88. Steinhoff BJ, Hübers E, Kurth C, et al. Plasma concentration and clinical
effects of perampanel – the Kork experience. Seizure. 2019;28:18–22.
89. Burns ML, Nikanorova M, Baftiu A, et al. Pharmacokinetic varia-
bility and clinical use of lacosamide in children and adolescents
in Denmark and Norway. Ther Drug Monit. 2019a;41
(3):340–347.
90. Contin M, Albani F, Riva R, et al. Lacosamide therapeutic monitor-
ing in patients with epilepsy: effect of concomitant antiepileptic
drugs. Ther Drug Monit. 2013;35(6):849–852.
91. May TW, Helmer R, Bien CG, et al. Influence of dose and antiepi-
leptic comedication on lacosamide serum concentrations in
patients with epilepsy of different ages. Ther Drug Monit. 2018;40
(5):620–627.
92. Johannessen Landmark C, Larsson PG, Rytter E, et al. Antiepileptic
drugs in epilepsy and other disorders: a population-based study of
prescriptions. Epilepsy Res. 2009;87:31–39.
93. Baftiu A, Johannessen Landmark C, Rudberg Rusten I, et al. Safety
aspects of utilization of antiepileptic drugs in epilepsy vs.
non-epilepsy disorders. Eur J Clin Pharmacol. 2016;72
(10):1245–1254.
94. Burns ML, Kinge E, Stokke Opdahl M, et al. Therapeutic drug
monitoring of gabapentin in various indications. Acta Neurol
Scand. 2019b;130(5):446–454.
95. Conway JM, Collins JF, Macias FM, et al. Factors in variability of
serial gabapentin concentrations in elderly patients with epilepsy.
Pharmacotherapy. 2017;37(10):1197–1203.
96. Bengtsson F. Therapeutic drug monitoring of psychotropic drugs.
TDM “nouveau”. Ther Drug Monit. 2004;26:145–151.
97. World Health Organization. Adherence to long term therapies –
evidence for action. World Health Organization 2003. Available
from: http://apps.who.int/iris/bitstream/handle/10665/42682/
9241545992.pdf
98. Davis KL, Candrilli SD, Edin HM. Prevalence and cost of nonadher-
ence with antiepileptic drugs in an adult managed care population.
Epilepsia. 2008;49:446–454.
99. Henning O, Johannessen Landmark C, Nakken KO, et al.
Nonadherence to treatment regimens in epilepsy from the
patients’ perspective and predisposing factors: differences
between intentional and non-intentional lack of adherence.
Epilepsia. 2019a;60(5):e58–e62.
100. Johannessen Landmark C, Fløgstad I, Syvertsen M, et al. Treatment
with AEDs and challenges for patients with JME. Epi Behav.
2019;98:110–116.
101. Henning O, Lossius MI, Lima MH, et al. Refractory epilepsy and
nonadherence to drug treatment. Epilepsia Open.
2019b;4:618–623.
102. Carpentier N, Jonas J, Frismand S, et al. Direct evidence of non-
adherence to antiepileptic medication in refractory focal epilepsy.
Epilepsia. 2013;54(1):e20–e23.
103. Lunardi M, Lin K, Walz R, et al. Single antiepileptic drug levels do
not predict adherence and nonadherence. Acta Neurol Scand.
2019;139(2):199–203.
104. Johannessen Landmark C, Fløgstad I, Baftiu A, et al. Long term
therapeutic drug monitoring of AEDs in patients with JME. Epilepsy
Res. 2019;155:106148.
105. Mevaag M, Henning O, Baftiu A, et al. Discrepancies between
physicians’ prescriptions and patients’ use of antiepileptic drugs.
Acta Neurol Scand. 2017;135:80–87.
106. Holtkamp M, Theodore WH. Generic antiepileptic drugs – safe or
harmful in patients with epilepsy? Epilepsia. 2018;59(7):1273–1281.
107. Kwan P, Arzimanoglou A, Berg AT, et al. Definition of drug resistant
epilepsy: consensus proposal by the ad hoc task force of the ILAE
12 C. JOHANNESSEN LANDMARK ET AL.
commission on therapeutic strategies. Epilepsia.
2010;51:1069–1077.
• Consensus document on treatment-resistant epilepsy.
108. Hao X, Goldberg D, Kelly K, et al. Uncontrolled epilepsy is not
necessarily the same as drug-resistant epilepsy: differences
between populations with newly diagnosed epilepsy and chronic
epilepsy. Epilepsy Behav. 2013;29(1):4–6.
109. Bialer M, Johannessen SI, Koepp MJ, et al. Progress report on new
antiepileptic drugs: a summary of the fourteenth Eilat conference on
new antiepileptic drugs and devices (EILAT XiV) II. Drugs in more
advanced clinical development. Epilepsia. 2018;59(10):1842–1866.
• Update on the development of AEDs that are undergoing clinical
studies.
110. Tomson T, Dahl M, Kimland E. Therapeutic monitoring of antiepileptic
drugs for epilepsy. Cochrane Database Syst Rev. 2007c;1:CD002216.
111. Fröscher W, Eichelbaum M, Gugler R, et al. A prospective rando-
mised trial on the effect of monitoring plasma anticonvulsant levels
in epilepsy. J Neurol. 1981;224:193–201.
112. Jannuzzi G, Cian P, Fattore C, et al. A multicenter randomized
controlled trial on the clinical impact of therapeutic drug
View publication stats
monitoring in patients with newly diagnosed epilepsy. Epilepsia.
2000;41:222–230.
113. Thangaratinam S, Marlin N, Newton S, et al. AntiEpileptic drug
monitoring in PREgnancy (EMPiRE): a double-blind randomized
trial on effectiveness and acceptability of monitoring strategies.
Health Technol Assess. 2018;22(23):1–152.
114. Chen Z, Liew D, Kwan P. Real-world efficiency of pharmacogenetic
screening for carbamazepine-induced severe cutaneous adverse
reactions. PLoS One. 2014;9(5):e96990.
•• Evidence for the efficiency of screening for mutations in order
to avoid carbamazepine-induced toxicity and thus avoiding
exposure to vulnerable patients.
115. Tassaneeyakul W, Prabmeechai N, Sukasem C, et al. Associations
between HLA class I and cytochrome P450 2C9 genetic polymorphisms
and phenytoin-related severe cutaneous adverse reactions in a Thai
population. Pharmacogenet Genomics. 2016;26(5):225–234.
116. Chouchi M, Kaabachi W, Tizaoui K, et al. The HLA-B*15:02 poly-
morphism and Tegretol®-induced serious cutaneous reactions in
epilepsy: an updated systematic review and meta-analysis. Rev
Neurol (Paris). 2018;174(5):278–291.