1. The clinical relevance adherence to therapy issues, substance
abuse history, and prior history of AED use.
Many of the new drugs are approved only for
of pharmacokinetics
adjunctive use; thus, polypharmacy and drug
interactions should also be considered.3
Pharmacokinetics has an important
role to play in the clinical use of AED
and drug interactions therapy.4 The term pharmacokinetics includes
the quantitative assessment of changes
of drug concentrations over time as a
with anti epileptic drugs function of the absorption, distribution,
metabolism and elimination processes.
These processes determine drug plasma
concentrations and in turn the drug plasma
therapeutic ranges.5 Pharmacokinetics
Janet Mifsud BPharm(Hons), PhD(QUB) is thus important in estimating the drug
dosage regimens necessary to achieve
drug plasma concentrations and predicting
Department of Clinical Pharmacology and Therapeutics, University of Malta the time to steady-state concentration
Email: janet.mifsud@um.edu.mt that will control seizures without causing
unacceptable toxicity.6 In this paper an
Keywords: pharmacokinetics, drug interactions, antiepileptic drugs, epilepsy overview will be given of how a knowledge of
pharmacokinetic mechanisms will determine
the ideal pharmacokinetic characteristics of
No single antiepileptic drug (AED) is appropriate in all clinical an AED, and an appreciation of the relevance
of parameters such as bioavailability,
situations and therapeutic decisions on the selection of the steady-state concentrations, protein-binding,
appropriate AED should be made on a variety of specific factors. metabolism and clearance in AED therapy.4,7
Pharmacokinetics has an important role to play in the clinical Various clinical factors such as age,
underlying physiological conditions and drug
practice of antiepileptic drug therapy, as it is important in estimating interactions will also affect efficacy of AED
individualised drug dosage regimens necessary to achieve drug plasma medication.2 Interaction among AEDs, and
concentrations without causing unacceptable toxicity. between AEDs and other classes of drugs,
can result in undesirable drug levels and
thus difficulty in achieving seizure control.5
In this paper an overview will be given Introduction By anticipating possible drug interactions
of how knowledge of pharmacokinetic Data from the World Health Organization or alterations in metabolism, adverse
mechanisms determines which indicate that as many as 1 in 20 people may effects and breakthrough seizures may
pharmacokinetic characteristics an AED have an epileptic seizure during their lives be averted. An awareness of AED clinical
should have. Various clinical factors such and that at least 1 in 200 people will have pharmacokinetics will thus aid the choice of
as age, underlying physiological conditions epilepsy.1 No single antiepileptic drug (AED) an appropriate drug and permits the design
and drug interactions will also affect the is appropriate in all clinical situations and of an optimal dosage schedule for each
pharmacokinetics and efficacy of AED epileptologists agree that proper seizure patient.8
medication. It will be shown how by diagnosis and classification is important
anticipating changes in pharmacokinetics in individualizing pharmacotherapy.2 What is Pharmacokinetics?
due to possible drug interactions, or Therapeutic decisions should be made on Pharmacokinetics is the quantitative
alterations in one of the pharmacokinetic a variety of specific factors such as seizure description of what happens to a drug
parameters, adverse effects and breakthrough type(s), onset of drug effect, the presence of when it enters the body, and includes the
seizures may be averted and aid in the renal or hepatic disease, possibility of drug processes of drug absorption, distribution,
choice of optimal AED therapy for each or disease state interactions, the possibility metabolism and elimination / excretion -
patient. of pregnancy, the age of the patient, ADME and how these processes affect the
drug plasma concentrations obtained.9
Figure 1. The relationship between pharmacokinetics and pharmacodynamics6
Pharmacokinetic Phase
Dose Absorption Interaction with Biological
Distribution Target Tissues Effect
Metabolism
Excretion Pharmacodynamic Phase
Issue 15 Summer 2009 Journal of the Malta College of Pharmacy Practice 23

2. Pharmacokinetics (PK) briefly is what These parameters can then be inputted skin, or from the site of an injection. Most
the body is doing to the drug; while into mathematical formulae that allow AEDs are administered orally since epilepsy
pharmacodynamics (PD) is what the drug is the estimation of the best dose of a drug is a chronic condition, and thus this will
doing to the body.9 in a specific patient depending on the enhance patient compliance.7 AEDs also
Pharmacodynamic effects include both pharmacokinetic parameters in that patient.7 exist as formulations that are available
wanted and unwanted drug pharmacological If multiple doses have to be administered for intravenous, intramuscular or rectal
effects. The underlying assumption is that the graph would change as represented in administration.9 Thus rectal administration
monitoring drug plasma concentrations is Figure 3. The plasma concentrations increase e.g. with rectal diazepam is useful as it
useful since they reflect drug concentration until, at the certain point, the minimum has been shown to terminate repetitive
at the receptor site, and thus being able and maximum plasma concentrations remain seizures in children with epilepsy and
to predict drug plasma concentrations is constant i.e. steady state is achieved.6 other disabilities, and can be administered
important since it will have a bearing on This usually takes about five half-lives and by family members at home.2 Intravenous
the dose required to obtain therapeutic drug depends on the volume of distribution administration e.g. phenytoin, phenobar­
concentrations. The individualisation of the and clearance of the drug. Ideally plasma bital, diazepam, lorazepam, levetiracetam
drug doses needed for specific patients as a concentrations at steady state should be and valproic acid are generally used for
result of varying pharmacokinetics is called within the therapeutic index for the drug i.e. emergencies such as status epilepticus since
clinical pharmacokinetics. Pharmacokinetics the concentration that achieves therapeutic the lengthy absorption phase is avoided.11
is useful because the basic principles are the effect, without going subtherapeutic or toxic With oral formulations, the rate of
same for all drugs.7 Figure 1. levels, in order to ensure that the drug is absorption and bioavailability varies widely
Plasma concentration time curves are a exerting its effect maximally.7 Figure 3. by drug, formulation, patient characteristics,
snap shot of what happens to the drug in the The pharmacokinetics of a drug are concomitant drugs, and food. Absorption
body. If we had to mathematically represent estimated in the first phases of drug can also be altered by drug interactions.12
what is happening a plasma concentration discovery. Ideally the drug should: Absorption depends also on the excipents
time curve is obtained.5 • Be soluble in 250ml water that make up the formulation, and in
Figure 2 represents what happens to a • Have a dose size < 500 mg fact differences between AEDs from
single dose of drug when given by any non- • Have complete passive absorption with different manufacturers may result in
iv route.6 The graph may be divided into 3 no transporters such as p-glycoprotein differences in bioavailability of the active
phases: involved in absorption/effusion drug. Thus changes in drug supply may
A: an initial absorption phase • Have bioavailability >80% result in breakthrough seizures.2 Calcium
B: a distribution phase • Have Linear PK containing antacids may interfere with
C: an elimination phase, which is linear if • Have a half-life of 8-12 h i.e. permits a phenytoin, phenobarbital, carbamazepine,
the plasma concentration axis is logged. twice daily dosing and gabapentin absorption by decreasing
• Have balanced hepatic/renal clearance the acidity of the stomach and also by the
This mathematical manipulation helps • Have low cytochrome (CYP450) formation of insoluble complexes that cannot
us to estimate various pharmacokinetic interactions with no cytochrome-2D6 be absorbed absorption.11 Gabapentin (but
parameters such as: metabolism not its chemical relative, pregabalin) is
• Ka rate of absorption • Have no active metabolites and no absorbed by a saturable amino acid transport
• Kel elimination rate constant genetic polymorphism in metabolic system and thus larger doses will cause
• Vd volume of distribution pathways.9,10 saturation.13
• T 1/2 half life of the drug Of particular concern is the issue of
• Cl drug clearance – generally renal Absorption concomitant administration of an AED
or hepatic Absorption is the entry of drug molecules with an enteral nutrition supplement.
• F bioavailability of the drug into the systemic circulation via the mucous Concomitant administration of phenytoin
membranes of the gut or lungs, via the with these nutritional formulations can result
in marked reductions in oral bioavailablilty
of this drug and it is commonly suggested
Figure 2. Plasma concentration time curve following a single dose not given by the IV route6 that the administration of phenytoin and
enteral feedings be separated by at least
2 hours.11 Unfortunately, this may not be
practical, particularly for patients requiring
continuous feedings. Alternatively, clinicians
can overcome this interaction by simply
increasing the phenytoin dosage, and using
serum drug concentrations as a guide.9
Co-administration of the newer AEDs such
as valproate, levetiracetam, lamotrigine or
gabapentin with enteral feeding supplements
A- mostly absorption; depends on ka, F does not appear to result in significant
B - mostly distribution; affected by %fu, Vd declines in AED serum concentrations.13
C- mostly elimination (renal/hepatic); Cl, t ½
Distribution
Following absorption into the general
circulation, the drug is distributed
throughout the body. The volume of
24 Journal of the Malta College of Pharmacy Practice Issue 15 Summer 2009

3. distribution is a virtual volume that gives Among the AEDs, the potential for Metabolism
an indication of the extent of distribution of protein-binding interactions is greatest Enzymatic biotransformation and
the drug to the various tissues. It may vary for phenytoin and valproic acid. Both metabolism is the principal determinant of
if the patient has liver or cardiac problems or phenytoin, and valproic acid are extensively the pharmacokinetic properties of most AEDs,
if the patient is pregnant.7 bound to plasma proteins (>90%). Valproic although some drugs are excreted by the
Drugs are generally protein bound, to acid is also an inhibitor of cytochrome kidneys predominantly as unchanged drug.2
a variable extent in the plasma, however P4502C19, one of the enzymes responsible Most AEDs exhibit linear enzyme kinetics, in
this process is reversible. It is the unbound for phenytoin metabolism.11 When these which clearance remains constant so changes
drug that crosses membranes and is thus two agents are co-adminis­ ered, unbound
t in daily dose lead to proportional changes
responsible for the drug’s action (both phenytoin concentrations are higher than in serum concentration. It is to be noted
therapeutic and toxic), so changes in expected and total concen­ rations are
t that some metabolites are themselves active
unbound, or free serum concentrations lower.9 In this setting, the clinician should (carbamazepine, oxcarbazepine, primidone).7
have the potential to cause unanticipated consider monitoring both unbound and The metabolic pathways of AEDs
effects.6 Drug-protein binding displacement total phenytoin concentrations.2 The most can vary, however, most metabolism is
interactions can occur when two highly important implication of this interaction achieved via oxidative metabolism and/
protein bound agents (>90%) are is that in the presence of valproic acid or glucuronidation.9 Oxidative metabolism
administered together and compete for the “therapeutic” range of total plasma occurs via the cytochrome P450 (CYP)
a limited number of binding sites.11 In phenytoin concentrations is shifted towards isoenzyme system. This system consists
most cases, protein binding displacement lower values.12 With the exception of of three main families of enzymes: CYP1,
interactions are transient clinical tiagabine (96% protein bound) an advantage CYP2, and CYP3. There are seven primary
events, however if only total drug serum of the newer generation AEDs is that they are isoenzymes that are involved in the
concentrations are being monitored, this not extensively protein bound, and therefore metabolism of most drugs: CYP1A2, CYP2A6,
may lead to misinterpretation of plasma drug in this group these types of pharmacokinetic CYP2C9, CYP2C19, CYP2D6, CYP2E1, and
levels.2 interactions are not likely.3 CYP3A4. Of these, those commonly involved
with metabolism of AEDs include CYP2C9,
Figure 3. Plasma concentration time curve following multiple doses given by the non IV route6 CYP2C19, and CYP3A4.14 Another important
metabolic pathway for several AEDs including
Cp valproic acid, lorazepam and lamotrigine
is conjugation via the enzyme uridine
diphosphate glucuronosyltransferase (UGT).13
By far the most important
pharmacokinetic interactions with AEDs are
those related to induction or inhibition of
drug metabolism.6
Enzyme induction is due to increased
synthesis of drug-metabolising isoenzymes
in the liver and in other tissues and may
be caused by carbamazepine, phenytoin,
and barbiturates. If the affected drug has
an active metabolite, enzyme induction can
result in increased metabolite concentration
and possible toxicity due to the metabolite.2
Enzyme inhibition is the phenomenon
by which a drug or its metabolite blocks the
Figure 4. Changes in phenytoin plasma concentration after increase in dose activity of one or more drug-metabolising
due to non linear kinetics 6 enzymes, which results in a decrease in the
rate of metabolism of the affected drug.
This, in turn, will lead to high plasma
concentrations of the drug and, possibly,
clinical toxicity.14
In some cases, AED-AED interactions are
bi-directional. In other words, both drugs
impact the pharmacokinetics of the other. In
general, enzyme inducers decrease the serum
concentrations of other drugs metabolized by
the same isoenzyme and enzyme inhibitors
have the opposite affect.8 The bi-directional
interaction between carbamazepine and
valproate is one common example. In this
setting, valproate can inhibit the enzyme
epoxide hydrolase, which is responsible for
the metabolism of the active metabolite
of carbamazepine, carbamazepine-
epoxide. Elevated carbamazepine -epoxide
concentrations have been associated
Issue 15 Summer 2009 Journal of the Malta College of Pharmacy Practice 25

4. with increased neurotoxicity. In addition complicate the management of other co- drugs such as pravastatin and rosuvastatin
carbamazepine can also significantly increase morbid disorders such as cardiovascular are not extensively metabolized, so
the metabolism of valproate, necessitating disease and affective disorders which more significant pharmacokinetic interactions
larger doses of this medication.2 commonly occur in the group of patients.12 with AEDs would not be anticipated.16
Other interactions may be of benefit The following sections provide an overview of Among the newer AEDs, only topiramate
in certain cases e.g. the synergistic effect potentially clinically meaningful interactions and oxcarbazepine appear to display modest
of valproic acid and lamotrigine which are that are likely to be encountered in practice. CYP3A4 inducing potential and thus the
metabo­ized by (UDP)-glucuronyltranferase.14
l Tables 1-2. potential for interactions between these
lipid-lowering drugs and AEDS is expected
Renal elimination Interactions of AEDs with drugs used in to be minimal. Unfortunately, at present no
Elimination is the removal of drug the treatment of hypertension studies have been performed to document
molecules from the body, usually by excretion The pharmacologic management this.11
of the parent drug or metabolites through of hypertension may require multiple
the kidneys. Drug elimination rate is usually antihypertensive drugs of differing classes. Interactions of AEDs with anticoagulants
expressed as the biological half-life and is Several commonly used antihypertensive Warfarin is administered as a racemic
defined as the time required for the serum medications may be susceptible to mixture of R- and S- enantiomers.
concentration to decrease by 50% following interactions with enzyme-inducing S-warfarin is exclusively metabolized via
absorption and distribution. The half- antiepileptic drugs.16 For example, lipophilic CYP2C9, while R-warfarin is metabolized
life also determines the dosing frequency beta antagonists such as propranolol and by several CYP isozymes including CYP1A2
required for a drug to be maintained at a metoprolol are extensively metabolized and CYP3A4.2 Since the S- enantiomer of
steady state in the serum.6 by several isozymes of the CYP system. warfarin is considerably more active than
Drugs that undergo extensive renal Therefore, larger doses of these medications the R- enantiomer, interactions involving
elimination in unchanged form may be might be required in patients receiving CYP2C9 are far more likely to have important
susceptible to interactions affecting the AEDs, which would be expected to increase clinical consequences. Carbamazepine
excretion process, particularly when it their rate of clearance.2 Conversely, fewer and phenobarbital can in fact reduce the
involves active transport mechanisms or potential interactions would be expected anticoagulant effect by increasing warfarin
when the ionised state of the drug is highly with the hydrophilic beta antagonists, such metabolism.16
sensitive to changes in urine pH, e.g. agents as atenolol and labetalol, which are primarily The interaction between warfarin and
that cause alkalisation of urine increase the renally excreted.15 phenytoin is far more complex. Initially,
elimination of phenobarbital by reducing the Another commonly used class of the coadministration of phenytoin may
reabsorption of this acidic drug from renal antihypertensive medication are the result in an increase in anticoagulant
tubuli.7 calcium channel antagonists. Drugs such effect, possibly due to the combined
Particular mention should be made as felodipine, nifedipine, nicardipine, effect of protein-binding displacement and
of phenytoin since it has unusual amlodipine, and nimodipine are members competitive inhibition of CYP2C92, causing a
pharmacokinetics which are saturable or of the dihydropyridine class of agents, and seemingly “paradoxical” anticoagulant effect
non-linear.6 In other words, unlike drugs these agents are extensively metabolized (i.e. increased prothrombin time, INR). In
that display linear elimination kinetics by CYP3A4. Concomitant treatment with the long term however, enzyme induction
(where changes in serum concentration enzyme inducers such as carbamazepine will probably lead to increased warfarin
are proportional to dose), phenytoin and phenytoin can result in substantial metabolism, necessitating increased warfarin
concentrations will show disproportionate reductions in the oral bioavailability of doses.11
changes in concentration following dose these medications.13 Other commonly used Clearly, in patients receiving warfarin
adjustment. In clinical terms, this suggests antihypertensive drugs such as diuretics and AED treatment, careful monitoring of
that dose adjustments with this medication and ACE inhibitors are not extensively international normalized ratios is crucial.
be small since increasing the dose by 50% metabolized, and thus would not be expected Whenever possible, this drug combination
could increase the plasma concentration four to interact with AEDs. should be avoided. Newer AEDS such as
fold. 2 gabapentin, pregabalin, lamotrigine,
Some AEDs eg gabapentin and pregabalin Interactions of AEDs with drugs used in levetiracetam and zonisamide do not appear
are only eliminated renally and do not the treatment of lipid disorders to interact with warfarin, and may be
undergo any metabolism.7 HMG-CoA reductase inhibitors safer (from a drug interaction viewpoint)
(“statins”) are among the most commonly alternatives.15,16
Drug interactions: impact of AED prescribed lipid-lowering medications.
treatment on commonly used Lovastatin, simvastatin, and atorvastatin Interactions of AEDs with drugs used in
medical therapies are metabolized extensively via CYP3A4. the treatment of depression
As has been explained, the occurrence Simvastatin and atorvastatin are also Most psychotropic drugs are metabolized
of pharmacokinetic interactions has the metabolized via glucuronidation (UGT by one or more of the CYP isozymes.14
potential to substantially complicate the 1A3) in both the gut and the liver. Therefore, co-medication with an inducing
management of the patient with epilepsy. Fluvastatin is metabolized by CYP2C9. drug would be expected to increase the
This may be particularly true when dealing All of these agents would therefore be metabolism, and therefore systemic clearance
with the elderly patient.8 In treating the expected to be susceptible to interaction of these medications. Serum concentrations
older patient with epilepsy, it is important with enzyme inducing AEDs.15 Indeed, one of tricyclic antidepressants such as
for the clinician to recognize that treatment pharmacokinetic study suggested that amitriptyline, nortriptyline, imipramine, and
with AEDs, particularly the older enzyme systemic exposure to simvastatin may be desipramine, as well as nontricyclics such as
inducing AEDs such as phenobarbital, reduced by nearly 80% in patients receiving sertraline, paroxetine, mianserin, citalopram,
phenytoin and carbamazepine15, may carbamazepine. Alternatively, other related and nefazodone, would be expected to be
26 Journal of the Malta College of Pharmacy Practice Issue 15 Summer 2009

5. reduced in patients receiving enzyme inducers.16 less likely to interact with the CYP isozyme half-lives relative to adults.2 Some children
Conversely, treatment with some SSRI system the likelihood of meaningful require almost twice the adult mg/kg dosage,
compounds has the potential to impact AED pharmacokinetic interactions is also reduced.11 particularly if combination therapy with
pharmacokinetics. For example, fluoxetine enzyme-inducers is employed.17
has been shown to inhibit several CYP Patient influences on drug Despite frequent drug administration,
isozymes, and concomitant treatment pharmacokinetics large swings in peak-to-peak concentrations
with phenytoin or carbamazepine may Various physiological and pathological are possible, especially in young children,
result in elevated serum concentrations of conditions can influence pharmacokinetic because of their fast elimination rates.18
those agents.2 In contrast to the inducers, and pharmacodynamic parameters.9 Solid oral dosage forms overcome this
valproate can inhibit certain CYP and UGT problem by providing a longer absorption
enzymes and may cause significant increases Children phase that reduces peak and increases
(50%-60%) in serum concentrations of Drug metabolism and disposition in trough concentrations. Crushed tablets are
antidepressants such as amitriptyline and children can differ significantly from that preferable to liquids in younger children for
nortriptyline.14 In some patients, this in adults.17 Beyond the neonatal period, similar reasons. Rapid gastrointestinal transit
increase may be sufficient to result in the when protein binding and drug metabolic times in children may, however, impede
emergence of adverse effects. Given that rates are low, children usually have faster absorption.17 In children, drug metabolism
many of the newer AEDs are, in general, drug elimination rates and reduced serum and disposition can differ significantly from
that in adults. Beyond the neonatal period,
Table 1. Effect of older AEDs on newer AEDs3,8,16 when protein binding and drug metabolic
rates are low, children usually have faster
gabapentin/ lamo- levetir- zonisa- drug elimination rates and reduced serum
pregabalin trigine topiramate tiagabine acetam mide Ox-carbazepine half-lives relative to adults.8 Some children
require almost twice the adult mg/kg dosage,
phenytoin none i i i none i mhd1 slt
particularly if combination therapy with
carbamazepine none i i i none i mhd slt
enzyme-inducers is employed. Furthermore,
valproic acid none i none none none none none because of shorter paediatric half-lives,
phenobarbital none i i i none i mhd slt most AEDs require at least three times daily
primidone none i i i none i mhd slt administration in children 1-10 years of age.13
Elderly
1: Monohydroxy-derivative In the elderly, AEDs should usually be
started at a lower dose and increased at
Table 2. Effect of newer AEDs on older AEDs3,8,16 a slower rate than in younger patients.18
Elimination of many drugs is slower in the
phenytoin carbamazepine valproic acid phenobarbital primidone elderly, mainly because of reduced hepatic
and renal blood flow, which lengthens drug
Gabapentin none none none none none
half-life above published values based on
Pregabalin young adults. In addition, albumin levels
lamotrigine none none i 25% none none fall with age; this increases the free fraction
topiramate may h none none none none of drugs that are highly protein bound, thus
tiagabine none none none none none increasing risk of toxicity, especially for
zonisamide none none none none none highly protein-bound drugs.17 Regarding the
levetiracetam none none none none none elderly, elimination of many drugs is slower,
oxcarbazepine none none none none none mainly because of reduced hepatic and renal
blood flow, which lengthens drug half-life
Table 3. Summary of PK characteristics of AEDS3,4,8,16 above published values based on young
adults.2 In addition, albumin levels fall with
Drug Absorption Elimination Half life Protein Causes age and this increases the free fraction of
(Hours) binding interactions drugs that are highly protein bound, thus
increasing risk of toxicity, especially for
Carbamazepine 80% 100% hepatic 6 -12 75-80% yes highly protein-bound drugs. Further, older
Valproic Acid 100% 90% hepatic 12-20 85-95%; yes people are often more sensitive to drug
Phenobarbitone 100% 75% hepatic 17-124 50% yes effects at a given free level. In the elderly,
Phenytoin 95%, 100% hepatic 12-60 70-95% yes AEDs should usually be started at a lower
Clobazebam 90%; 100% 10-50 83% yes dose and increased at a slower rate than in
Gabapentin < 60% 100% renal 5-8 0% no younger patients.8
Flebamate well absorbed 40-49% renal 13-30 20-25% yes
Lamotrigine 98% 100% hepatic 18-30 55% yes Pregnancy
Pregnancy increases the volume of
Levetiracetam 100% 66% renal 4-8 <10% no
distribution and the rate of drug metabolism,
Oxcarbazepine (MHD) 100% 100% hepatic 5-11 40% yes and decreases protein binding. For most
Pregabilin 90% 90% renal no AEDs, the optimal dose increases as
Tiagabine 96%. 97% hepatic 5-13 96% no pregnancy progresses.2 It is also noteworthy
Topiramate >80%; 30-55% renal 18-30 15% yes that in cases of pregnancy, the volume of
Zonisamide 80-100% 50-70% hepatic 50-80 40-60%. no distribution and the rate of drug metabolism
Issue 15 Summer 2009 Journal of the Malta College of Pharmacy Practice 27

6. are increased whereas protein binding is
decreased. For most AEDs, the optimal dose
increases as pregnancy progresses.19 • Pharmacokinetics is the quantitative description of what happens to a drug when it
enters the body, and is important in estimating the drug dosage regimens necessary to
Others
Fever can increase the metabolic rate, achieve drug plasma concentrations without causing unacceptable toxicity.
resulting in more rapid drug elimination and • Knowledge of pharmacokinetic mechanisms will determine the ideal pharmacokinetic
lower serum con­ entrations. Febrile illnesses
c characteristics of an AED, and an appreciation of the relevance of parameters such as
may also elevate serum proteins that bind bioavailability, steady-state concentrations, protein-binding, metabolism and clearance
AEDs, resulting in decreased free levels.2 in AED therapy.
Severe hepatic disease impairs • Various clinical factors such as age, underlying physiological conditions and drug
metabolism, increasing serum levels and risk interactions will also affect efficacy of AED medication.
of toxicity of many drugs. However, complex • Interaction among AEDs, and between AEDs and other classes of drugs, can result
interactions among hepatic blood flow, in undesirable drug levels and thus difficulty in achieving seizure control. By
biliary excretion, and hepatocellular function anticipating possible drug interactions or alterations in metabolism, adverse effects and
make the net effect of hepatic disease on
breakthrough seizures may be averted.
drug levels difficult to predict.18
Renal disease reduces elimination of • An awareness of AED clinical pharmacokinetics will thus aid the choice of an appropriate
some drugs such as gabapentin. In chronic drug and permits the design of an optimal dosage schedule for each patient.
renal disease where there is protein loss, one
can commonly see a higher free fraction of antiepileptic drugs for several reasons.9 that drug interactions may occur not only
highly protein bound AEDs which then are Patients with epilepsy generally require when an inducer or inhibitor is added to
more susceptible to elimination lower serum chronic therapy, and, therefore, a dosing a patient’s medication regimen, but also
concentration of the drug. More frequent Practice points
strategy that enhances compliance is when the inducing (e.g. carbamazepine) or
doses may need to be given. Effects of essential. Also, many patients will be inhibiting (e.g. valproate) agent is removed.
dialysis differ among AEDs. Some, such as prescribed two or more antiepileptic drugs, Removal of an enzyme-inducing drug
phenobarbital, are significantly removed.2 often times at the highest possible doses.8 will result in “deinduction,” and if doses
Table 3. Additionally, all patients with chronic are not adjusted, serum concentrations of
epilepsy can be expected to develop during many metabolized concomitant drugs may
PK parameters and drug interactions of their lifetime concomitant nonepilepsy- increase.2 Loss of enzyme induction can
AEDs: which way to go? related diseases that require additional drug occur with days to several weeks following
Determining the pharmacokinetics and therapy, increasing the potential for drug discontinuation of the inducing drug. Given
the avoidance of durg-drug interactions interactions and toxicity. Thus, it is desirable that it will take about five half-lives for the
are useful selection criteria for AED that the drugs do not cause interactions that previously induced medication to reach a
selection. Indeed, the characterization of can precipitate toxicity.13 new steady-state level, these de-induction
the clinical pharmacokinetic profile of a new Finally, it is important to recognize that interactions may have an insidious onset.10
antiepileptic drug is an integral and early drug interactions are not a “one-way street”. Thus good knowledge of the
component of drug development.9 Interactions can be bi-directional, meaning pharmacokinetic mechanisms of the various
Consequently, pharmacokinetic that two drugs can influence each other.18 AEDs will significantly aid the decision of
considerations are especially relevant with In addition, another important concept is which dosing strategy is the most efficient
and enhance clinical therapy of AEDs.
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