Download EpilEpsy BoARD REviEw MAnuAl Antiepilepsy Drugs: Mechanisms

Epilepsy Board Review Manual
Statement of
Editorial Purpose
The Epilepsy Board Review Manual is a study
guide for trainees and practicing physicians
preparing for board examinations in epilepsy.
Each manual reviews a topic essential to the
current management of patients with epilepsy.
Antiepilepsy Drugs: Mechanisms
of Action and Pharmacokinetics
Contributor and Editor:
Thomas R. Henry, MD
Professor of Neurology, Director, Comprehensive
Epilepsy Center, University of Minnesota Medical School,
Minneapolis, MN
PUBLISHING STAFF
PRESIDENT, Group PUBLISHER
Contributor:
Jeannine M. Conway, PharmD
Assistant Professor of Pharmacy, University of Minnesota
College of Pharmacy, Minneapolis, MN
Bruce M. White
Senior EDITOR
Robert Litchkofski
executive vice president
Barbara T. White
executive director
of operations
Jean M. Gaul
Table of Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
Mechanism of Action . . . . . . . . . . . . . . . . . . . . . . 1
Pharmacokinetics. . . . . . . . . . . . . . . . . . . . . . . . . 2
NOTE FROM THE PUBLISHER:
This publication has been developed with­
out involvement of or review by the Amer­
ican Board of Psychiatry and Neurology.
Board Review Questions. . . . . . . . . . . . . . . . . . . 10
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
Antiepilepsy Drugs: Mechanisms of Action and Pharmacokinetics
Epilepsy Board Review Manual
Antiepilepsy Drugs:
Mechanisms of Action and Pharmacokinetics
Jeannine M. Conway, PharmD, and Thomas R. Henry, MD
Introduction
Epilepsy therapy almost always includes chronic use of one or more medications. As such, the
treating epileptologist must be expert in selecting
antiepileptic drugs (AEDs) and monitoring the
patient’s response to therapy over time. Epileptologists must be able to: (1) select antiseizure
medications, both for the syndrome and for
the individual's clinical situation, which includes
avoiding AEDs likely to cause adverse effects
in particular patient groups as well as avoiding
redundancy of AED mechanisms in polytherapy;
(2) initiate and maintain AED dosing chronically
and in status epilepticus; (3) recognize and avoid
dangerous AEDs and unnecessary AED intolerability; and (4) analyze response failure and AEDs
with reference to serum levels and absorptionelimination mechanisms.
There are approximately 22 AEDs currently
available in the United States. Prior to 1993, the
primary AEDs were phenobarbital, phenytoin,
carbamazepine, and valproic acid. Since 1993,
numerous medications have become available,
allowing providers to better customize pharma-
cotherapy to the individual patient. The newer
AEDs are referred to as second- and thirdgeneration AEDs. An understanding of the various agents along with their pharmacokinetic
characteristics and side-effect profiles allows the
prescriber to best tailor medication selection for
a patient. This article reviews the mechanisms of
action and pharmacokinetics of the AEDs, and
the subsequent article in this series will review
their pharmacodynamics.
Mechanism of action
For most AEDs, the mechanisms by which they
exert an anticonvulsant effect are not entirely understood. The primary mechanisms of action for
these drugs involve decreasing the excitation of
neurons by blocking sodium and/or calcium channels or antagonizing glutamate receptors. Some
medications increase the inhibition of neurons
by increasing or enhancing γ-aminobutyric acid
(GABA).1 The mechanisms of action of the currently available AEDs are summarized in Table 1.
Visual representations of AED mechanisms at the
synapse are presented in Figure 1 and Figure 2.2
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www.turner-white.comEpilepsy Volume 1, Part 5 1
Antiepilepsy Drugs: Mechanisms of Action and Pharmacokinetics
Table 1. Mechanisms of Antiepileptic Drugs
Medication
Ion Channel
First generation
Benzodiazepines
Carbamazepine
Ethosuximide
Phenobarbital
Na, Ca (L-type) blockade
Ca (T-type) blockade
Increases chloride ion influx
Na blockade
Na?/Ca (L-type) blockade
Gabapentin
Lamotrigine
Ca (N-, P/Q-type)
Na/Ca (N-, P/Q-, R-, T-type)
blockade
K?/Ca (N-type) blockade
Na/Ca (N- and P-type)
blockade
Ca (N-, P/Q-type) blockade
Na prolonged inactivation
Pregabalin
Rufinamide
Tiagabine
Topiramate
Vigabatrin
Zonisamide
Third generation
Ezogabine
Lacosamide
Inhibitory Mechanism
Other
Enhances GABA
Phenytoin
Valproic acid
Second generation
Felbamate
Levetiracetam
Oxcarbazepine
Excitatory Mechanism
Na/Ca blockade
Na blockade
Enhances and
increases GABA
Antagonizes NMDA
receptors
Increases GABA
Increases GABA
Antagonizes AMPA/kainate
glutamate receptor
Increases GABA
Enhances GABA
Binds to SV2A protein
Inhibits carbonic anhydrase
enzyme
Increases GABA
Na/Ca (N-, P-, T-type) blockade
Inhibits carbonic anhydrase
enzyme
K (enhances M-type current)
Increases slow inactivation
of Na channels
Binds to collapsin response
mediator protein-2
Perampanel
Antagonizes AMPA
glutamate receptor
Adapted with permission from Perucca E. An introduction to antiepileptic drugs. Epilepsia 2005;46 Suppl 4:31–7.
Ca = calcium; GABA = γ-aminobutyric acid; K = potassium; Na = sodium.
Pharmacokinetics
After a medication is administered, the body
begins to redistribute, sequester, modify, and
eliminate it. An understanding of pharmacokinetics allows the prescriber to select the best drug
for a patient considering their current medica2 Hospital Physician Board Review Manual
tions, comorbidities, and medication preferences.
The ideal drug, whether used for epilepsy or any
other condition, should be completely absorbed,
minimally bind to proteins, distribute into the site
of action, have minimal hepatic metabolism (and
not interfere with the metabolism of other medications), and be eliminated by the kidney so that
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Antiepilepsy Drugs: Mechanisms of Action and Pharmacokinetics
Figure 1. Diagram of an excitatory synapse in the central nervous
system and the sites of action for various anticonvulsants. (Adapted with permission from Rho JM, Sankar R. The pharmacologic
basis of antiepileptic drug action. Epilepsia 1999;49:1471–83.)
Figure 2. Diagram of an inhibitory synapse in the central nervous
system and the sites of action of various anticonvulsants. (Adapted with permission from Rho JM, Sankar R. The pharmacologic
basis of antiepileptic drug action. Epilepsia 1999;49:1471–83.)
predictions about clearance can be made for
an individual patient. Additionally, the dose and
blood levels should have a linear relationship;
for example, when a dose is doubled, the blood
level doubles predictably. Many of the currently
available AEDs lack these desired characteristics
(Table 2, Table 3, and Table 4).
There are 4 principles of pharmacokinetics that
should be considered when comparing and contrasting AEDs: absorption, distribution, metabolism,
and elimination. Absorption is the movement of a
drug molecule from the gut into blood to be circulated
into other tissue(s).3 Absorption is described by the
Tmax (time to maximal peak blood levels) and the
Cmax (the maximal concentration observed) in
pharmacokinetic characterization studies. These
parameters are important for determining bioavailability.4 Medications may be passively absorbed, or
transporters may be involved. One of the most clinically relevant examples of transporter involvement
in absorption is gabapentin, whose absorption is
limited by saturation of the L-amino acid trans-
porter whereby the percentage of a dose absorbed
decreases as the dose increases.5 Adjustments
in the frequency and amount of gabapentin dose
can be made, with smaller doses administered
more frequently, to optimize the absorption. There
are a number of other gut transporters, including
P-glycoprotein and organic anion transporting
polypeptide, that may also play a role in drug interactions.6 Changes in gut function, particularly
rapid transit time or shortened intestines due to
surgery, may radically reduce absorption. This can
significantly impact the absorptions of medications delivered in an extended-release formulation,
which require a sufficient amount of time in the gut
or a specific environment, such as a certain pH, to
be absorbed. Patients who have undergone a gastric bypass procedure may experience changes
in their pharmacokinetics and require close monitoring, although the data in this area is currently
limited.7
After a drug is absorbed, it is distributed throughout the body. Distribution consists of 2 factors: how
www.turner-white.comEpilepsy Volume 1, Part 5 3
Antiepilepsy Drugs: Mechanisms of Action and Pharmacokinetics
Table 2. Drug Interactions Between Antiepileptic Drugs (AEDs)
Initial AED
Added AED
Effect
Carbamazepine
Felbamate
Decrease carbamazepine plasma levels
Increase carbamazepine epoxide levels
Decrease carbamazepine plasma levels
Decrease carbamazepine plasma levels
Decrease carbamazepine plasma levels
Clobazam
Ethosuximide
Ezogabine
Felbamate
Gabapentin
Lacosamide
Lamotrigine
Levetiracetam
Oxcarbazepine
Perampanel
Phenobarbital
Phenytoin
Phenobarbital
Phenytoin
Rufinamide*
No clinically significant interactions
Carbamazepine
Phenobarbital
Phenytoin
Valproic acid
Phenytoin
Carbamazepine
Carbamazepine
Phenytoin
Valproic acid
No known interactions
No known interactions
Carbamazepine
Phenobarbital
Phenytoin
Primidone
Rufinamide*
Valproic acid
No known interactions
Carbamazepine
Phenytoin
Phenobarbital
Carbmazepine
Oxcarbazepine
Phenobarbital
Phenytoin
Felbamate
Phenytoin
Rufinamide*
Valproic acid
Carbamazepine
Clobazam
Felbamate
Methsuximide
Phenobarbital
Rufinamide*
Valproic acid
Vigabatrin
Decrease ethosuximide plasma levels
Decrease ethosuximide plasma levels
Decrease ethosuximide plasma levels
Increase ethosuximide plasma levels
Decrease ezogabine plasma levels
Decrease ezogabine plasma levels
Decrease felbamate plasma levels
Decrease felbamate plasma levels
Increase felbamate plasma levels
Decrease lamotrigine plasma levels
Decrease lamotrigine plasma levels
Decrease lamotrigine plasma levels
Decrease lamotrigine plasma levels
Decrease lamotrigine plasma levels
Increase lamotrigine plasma levels
Decrease active metabolite
Decrease active metabolite
Decrease active metabolite
Decrease perampanel plasma levels
Decrease perampanel plasma levels
Decrease perampanel plasma levels
Decrease perampanel plasma levels
Increase phenobarbital levels
Increase or decrease phenobarbital levels
Increase phenobarbital levels
Increase phenobarbital levels
Decrease phenytoin plasma levels
Increase phenytoin plasma levels
Increase phenytoin plasma levels
Increase phenytoin plasma levels
Increase or decrease phenytoin plasma levels
Increase phenytoin plasma levels
Decrease total phenytoin levels; unchanged or slightly increased free
phenytoin levels
Decrease phenytoin plasma levels
(Continued on page 5)
*Drug interactions on AED concentrations observed in pediatric populations, with little effect on AED concentrations in adult population.
4 Hospital Physician Board Review Manual
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Antiepilepsy Drugs: Mechanisms of Action and Pharmacokinetics
Table 2. Drug Interactions Between Antiepileptic Drugs (AEDs) (continued)
Initial AED
Added AED
Effect
Pregabalin
Primidone
No known interactions
Carbamazepine
Phenytoin
Valproic acid
Carbamazepine*
Phenobarbital*
Phenytoin*
Primidone*
Valproic acid*
Carbamazepine
Phenobarbital
Phenytoin
Carbamazepine
Phenobarbital
Phenytoin
Valproic acid
Carbamazepine
Felbamate
Lamotrigine
Phenobarbital
Primidone
Phenytoin
Topiramate
Carbamazepine
Phenytoin
Phenobarbital
Decrease primidone; increase phenobarbital
Decrease primidone; increase phenobarbital
Increase primidone; increase phenobarbital
Decrease rufinamide plasma levels
Decrease rufinamide plasma levels
Decrease rufinamide plasma levels
Decrease rufinamide plasma levels
Increase rufinamide plasma levels
Decrease tiagabine plasma levels
Decrease tiagabine plasma levels
Decrease tiagabine plasma levels
Decrease topiramate plasma levels
Decrease topiramate plasma levels
Decrease topiramate plasma levels
Decrease topiramate plasma levels
Decrease valproic acid serum levels
Increase valproic acid serum levels
Decrease valproic acid (slightly) serum levels
Decrease valproic acid serum levels
Decrease valproic acid serum levels
Decrease valproic acid serum levels
Decrease valproic acid serum levels
Decrease zonisamide serum levels
Decrease zonisamide serum levels
Decrease zonisamide serum levels
Rufinamide
Tiagabine
Topiramate
Valproic acid
Zonisamide
Adapted from Dipiro J, Talbert RL, Yee G, et al. Pharmacotherapy: a pathophysiologic approach. 8th ed. New York (NY): McGraw-Hill; 2011.
*Drug interactions on AED concentrations observed in pediatric populations, with little effect on AED concentrations in adult population.
much drug is bound to proteins and how much drug
is distributed into tissues.8 If a medication is highly
polar, it will primarily remain in the extracellular fluid.
If a medication is lipophilic, it will more likely distribute
into tissue compartments. The volume of distribution
(Vd) is used to calculate loading doses:
Loading dose = (concentration desired – baseline
concentration) × wt in kg × Vd (L/kg)
This equation is useful for estimating doses when a
patient needs a new medication started rapidly or if
their blood level is low and it needs to be increased.
Metabolism is the enzymatic reaction(s) that
occur(s) to a drug as the body is detoxifying itself.
The majority of drug metabolism occurs in the liver.
Phase I reactions are catalyzed by the cytochrome
P-450 (CYP) family of enzymes, resulting in oxidized, reduced, or hydroxylated metabolites. Phase
II reactions create polar metabolites that are more
easily excreted into urine or bile. Either the parent
drug or the metabolite from the phase I reaction can
be glucuronidated (phase II) for elimination.9
Most medications (or their metabolites) are
finally eliminated from the body via the kid-
www.turner-white.comEpilepsy Volume 1, Part 5 5
Antiepilepsy Drugs: Mechanisms of Action and Pharmacokinetics
Table 3. Antiepileptic Drug (AED) Interactions With Other Drugs
AED
Drug
Interaction
Carbamazepine
Cimetidine
Erythromycin
Fluoxetine
Isoniazid
Hormonal contraceptives
Doxycycline
Theophylline
Warfarin
Nefazodone
Hormonal contraceptives
Ketoconazole
Digoxin
Antacids
No clinically significant interactions
Hormonal contraceptives
Hormonal contraceptives
Cyclosporine
CYP 3A4 inducers (rifampin, St. Johns wort)
Hormonal contraceptives
Acetazolamide
Hormonal contraceptives
Amiodarone
Antacids
Cimetidine
Chloramphenicol
Disulfiram
Ethanol (acute)
Fluconazole
Fluoxetine
Isoniazid
Warfarin
Ethanol (chronic)
Hormonal contraceptives
Bishydroxycoumarin
Folic acid
Quinidine
Vitamin D
Increase carbamazepine plasma level
Increase carbamazepine plasma level
Increase carbamazepine plasma level
Increase carbamazepine plasma level
Decrease hormonal contraceptives efficacy
Decrease doxycycline efficacy
Decrease theophylline efficacy
Decrease warfarin efficacy
Decrease nefazodone and increase carbamazpine plasma level
Decrease hormonal contraceptives efficacy
Increase clobazam
Increase digoxin concentrations due to inhibition of P-glycoprotein transport
Decrease gabapentin absorption (take 2 hours apart)
Clobazam
Ezogabine
Gabapentin
Lacosamide
Lamotrigine
Oxcarbazepine
Perampanel
Phenobarbital
Phenytoin
6 Hospital Physician Board Review Manual
Decrease lamotrigine plasma levels
Decrease hormonal contraceptives efficacy
Decrease cyclosporine concentrations
Decrease perampanel plasma levels
Decrease hormonal contraceptives efficacy
Increase phenobarbital concentrations
Decrease hormonal contraceptives efficacy
Increase phenytoin concentrations
Decrease phenytoin concentrations
Increase phenytoin concentrations
Increase phenytoin concentrations
Increase phenytoin concentrations
Increase phenytoin concentrations
Increase phenytoin concentrations
Increase phenytoin concentrations
Increase phenytoin concentrations
Can both increase/decrease INR
Decrease phenytoin concentrations
Decrease hormonal contraceptives efficacy
Decrease anticoagulation
Decrease folic acid
Decrease quinidine
Decrease vitamin D
(Continued on page 7)
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Antiepilepsy Drugs: Mechanisms of Action and Pharmacokinetics
Table 3. Antiepileptic Drug (AED) Interactions With Other Drugs (continued)
AED
Drug
Interaction
Primidone
Isoniazid
Nicotinamide
Chlorpromazine
Corticosteroids
Quinidine
Tricyclic antidepressants
Furosemide
Hormonal contraceptives
Triazolam
Hormonal contraceptives
Cimetidine
Salicylates
Decrease metabolism of primidone
Decrease metabolism of primidone
Decrease chlorpromazine
Decrease corticosteroids
Decrease quinidine
Decrease tricyclic antidepressants
Decrease renal sensitivity to furosemide
Decrease hormonal contraceptives efficacy
Decrease triazolam AUC by 37% and peak concentration by 23%
Decrease hormonal contraceptives efficacy
Increase valproic acid concentrations
Increase free valproic acid concentrations
Rufinamide
Topiramate
Valproic acid
Adapted from DiPiro JT, Talbert RL, Yee GC, et al. Pharmacotherapy: a pathophysiologic approach. 6th ed. New York (NY): McGraw-Hill; 2005.
AUC = area under the concentration-time curve.
neys into the urine. Glomerular filtration can
be estimated with a variety of formulas using
serum creatinine levels, including the Modification of Diet in Renal Disease study equation (MDRD), the Cockcroft-Gault equation, and
most recently, the Chronic Kidney Disease Epidemiology Collaboration equation (CKD-Epi).10
The MDRD and CKD-Epi are used to stage kidney function.11,12 The Cockcroft-Gault equation
is frequently used for estimating kidney function when drug dose adjustments are required.13
With the validation of new equations, some pharmaceutical companies have used methods other
than the Cockcroft-Gault to renally adjust their
products. As a result, each provider should refer to
the prescribing information to verify if and how adjustments are made for declining kidney function.
Human physiology changes over the life span
and, as a result, the pharmacokinetics for a given
patient on a given medication also will change
over the life span. As patients age, increases in
fat tissues and decreases in lean body mass im-
pact volume of distribution.14 Kidney function also
declines with age.15,16 Pregnancy in particular may
alter hepatic function, with prominent effects on
AED elimination that may require significant dosing
changes to maintain effective serum concentrations of an agent such as lamotrigine.17
Drug-drug and drug-disease
interactions
Drug interactions are frequently the result of
an alteration of pharmacokinetics. In the case of
AEDs, alterations in absorption and metabolism
are the most common causes of drug interactions. Absorption interactions can be caused
by 2 medications binding to each other, resulting in a chelate that cannot be absorbed.
Tissues in the gastrointestinal tract express
CYP enzymes and P-glycoprotein, both of which
can be inhibited or induced.18,19 If CYP enzymes
are inhibited, more medication can be absorbed
from the gut, increasing exposure. If CYP enzymes are induced, more drug is metabolized in
www.turner-white.comEpilepsy Volume 1, Part 5 7
Antiepilepsy Drugs: Mechanisms of Action and Pharmacokinetics
Table 4. Antiepileptic Drug (AED) Pharmacokinetics in Non-Induced Patients
Medication
First generation
Carbamazepine
Ethosuximide
Phenobarbital
Phenytoin
Valproic acid
Second generation
Clobazam
Felbamate
Gabapentin
Lamotrigine
Levetiracetam
Oxcarbazepine
Pregabalin
Rufinamide
Tiagabine
Topiramate
Vigabatrin
Zonisamide
Third generation
Ezogabine
Lacosamide
Perampanel
Absorbed (%)
Binding (%)
Elimination
Half-life (hr)
Vd (L/kg)
Interactions with
Other AEDs
80
Well absorbed
100
95
100
75–85
Insignificant
50
90
80–90
100% hepatic
80% hepatic
75% hepatic
100% hepatic
100% hepatic
6–15
25–60
72–124
12–60
6–18
0.8–2
0.62–0.72
0.5–1
0.5–1
0.14–0.23
Bi-D
Uni-D
Bi-D
Bi-D
Bi-D
100
90
<60*
98
100
~100
>90
85*
90
>80
100
80–100
80–90
25
0
55
10
40
0
34
96
15
0
40–60
98% hepatic
55% hepatic
100% renal
100% hepatic
Hydrolysis
60%–90% hepatic
98% renal
98% hepatic
100% hepatic
50%–70% renal
95% renal
50%–70% hepatic
36–42
20–23
5–9
25–32
6–8
5–13
5–6.5
6–10
7–9
21
7.5
63
1.4–1.8
0.7–1
0.65–1.4
0.9–1.3
0.7
0.7
0.5
0.7–1.1
0.74–0.85
0.6–0.8
0.8
1.45
Uni-D
Bi-D
None
Bi-D
None
Bi-D
None
Bi-D
Uni-D
Bi-D
Uni-D
Uni-D
60
100
100
80
<15
96
60% hepatic
40% renal
Extensive hepatic
7–11
13
105
2–3
0.6
Not reported
Bi-D
None
Uni-D
*Saturable absorption, so that percentage absorbed decreases with increasing doses.
Bi-D = causes and is affected by drug interactions; Uni-D = affected by other medications; Vd = volume of distribution.
the gut, resulting in less absorption. P-glycoprotein
is an efflux transporter located on the enterocytes that pumps medications back into the gut.
Inhibition of P-glycoprotein results in an increase
of absorption, while induction will result in a
decrease of absorption. P-glycoprotein is also
found in other tissues, including kidneys, pancreas,
and the blood-brain barrier.20 The mechanisms for
metabolism (predominately in the liver) interactions are enzyme inhibition or enzyme induction.
Hepatic inhibition occurs when the interacting drug
competes for binding on the enzyme, resulting in
8 Hospital Physician Board Review Manual
decreased clearance of the affected drug. Hepatic
induction occurs when there is an increase in the
amount of enzyme available, resulting in increased
clearance of the affected drug.21 Older AEDs
(phenobarbital, phenytoin, and carbamazepine)
are some of the most common enzyme-inducing
medications used, and they interact with a wide
variety of medications.22 See Table 2 and Table 3
for interactions involving AEDs.
Beyond pharmacokinetic drug interactions,
some medications may lower seizure threshold
and should be used with caution, including tramadwww.turner-white.com
Antiepilepsy Drugs: Mechanisms of Action and Pharmacokinetics
ol, bupropion (at higher doses and when using the
immediate-release formulation), and clozapine.23-26
Dalfampridine, the newly approved medication for
improving walking distance for patients with multiple sclerosis, has been reported to cause seizures
in patients taking the recommended doses.27
Therapeutic monitoring
Ideally, for each AED there is a clear correlation
between its dose, blood concentration, and clinical
effect. Early research on older AEDs, particularly
phenytoin, did demonstrate a relationship between
blood concentration and clinical effect.28–30 It is
now recognized that not all patients will achieve
seizure control in the therapeutic range of their
respective AED(s).31,32 Some patients will achieve
seizure control below the low end of the therapeutic range, and some will require much higher
blood levels to achieve seizure control. Evidence to
support regular blood level monitoring of AEDs is
lacking.33 However, many clinicians use blood
levels to establish an individual patient’s therapeutic range. If a patient is achieving good control,
measuring the patient’s AED blood level may be
warranted to understand their individual dose concentration relationship. If that patient becomes ill
(or nonadherent, experiences a drug interaction),
has a seizure, and a blood test shows the AED
concentration is a fraction of the usual blood level,
that may provide some insight into why the patient had the seizure. Additionally, if a patient has
a breakthrough seizure despite consistent AED
blood levels, adding an AED or switching an AED
in the patient’s regimen may be warranted.
BOARD REVIEW QUESTIONS
Test your knowledge of this topic.
Go to www.turner-white.com and select Epilepsy
from the drop-down menu of specialties.
10 Hospital Physician Board Review Manual
References
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2005;46 Suppl 4:31–7.
2. Rho JM, Sankar R. The pharmacologic basis of antiepileptic drug action. Epilepsia 1999;49:1471–83.
3. Fleisher D, Li C, Zhou Y, et al. Drug, meal and formulation interactions influencing drug absorption after oral
administration. Clinical implications Clin Pharmacokinet
1999;36:233–54.
4. Johannessen Landmark C, Johannessen SI, Tomson T.
Host factors affecting antiepileptic drug delivery-pharmacokinetic variability. Adv Drug Deliv Rev 2012;64:896–910.
5. Stewart BH, Kugler AR, Thompson PR, Bockbrader HN.
A saturable transport mechanism in the intestinal absorption of gabapentin is the underlying cause of the lack of
proportionality between increasing dose and drug levels in
plasma. Pharm Res 1993;10:276–81.
6. Müller F, Fromm MF. Transporter-mediated drug-drug interactions. Pharmacogenomics 2011;12:1017–37.
7. Edwards A, Ensom MH. Pharmacokinetic effects of bariatric surgery. Ann Pharmacother 2012;46:130-6.
8. Jusko WJ, Gretch M. Plasma and tissue protein binding of
drugs in pharmacokinetics. Drug Metab Rev 1976;5:43–140.
9. Wilkinson GR. Drug metabolism and variability among patients in drug response. N Engl J Med 2005;352:2211–21.
10. National Kidney Foundation. Frequently asked questions
about GFR estimates. http://www.kidney.org/professionals/
kls/pdf/12-10-4004_KBB_FAQs_AboutGFR-1.pdf
11. Levey AS, Bosch JP, Lewis JB, et al. A more accurate
method to estimate glomerular filtration rate from serum
creatinine: a new prediction equation. Modification of
Diet in Renal Disease Study Group Ann Intern Med
1999;130:461–70.
12. Levey AS, Stevens LA, Schmid CH, et al; for the CKD-EPI
(Chronic Kidney Disease Epidemiology Collaboration). A
new equation to estimate glomerular filtration rate. Ann
Intern Med 2009;150:604–12.
13. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976;16:31–41.
14. Forbes G, Reina J. Adult lean body mass declines
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