16 - Levetiracetam

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16: Levetiracetam
INTRODUCTION
Levetiracetam is a pyrrolidinebased compound effective in the management of partial and tonicclonic seizures, and it is administered as the S
enantiomer of a stereoisomer pair (Table 161).1,2,3, and 4 It is also useful for the treatment of myoclonic seizures in patients with juvenile myoclonic
epilepsy. Levetiracetam does not exhibit antiseizure properties in all models used to screen antiepileptic drugs, and its exact mechanism of action is
largely unknown. It does bind to a synaptic vesicle protein, SV2A, present in brain tissue, and this action is thought to be important to its therapeutic
actions.5,6
TABLE 161
International Classification of Epileptic Seizures With Recommended Therapies
Major Class Subset of Class Drug Treatment for Selected Seizure Type
2004 2013 Medical

2012 NICE 2013 ILAEa
AAN/AES Letter
Partial seizures (beginning 1. Simple partial seizures (without Carbamazepine Lamotrigine Carbamazepine Adults:
locally) impaired consciousness) Phenytoin Carbamazepine Lamotrigine Carbamazepine
a. with motor symptoms Valproate Levetiracetam Levetiracetam Levetiracetam
b. with somatosensory or special Phenobarbital Oxcarbazepine Oxcarbazepine Phenytoin
sensory symptoms Lamotrigine Alternatives: Valproate Zonisamide
c. with autonomic symptoms Gabapentin Topiramate Adjunctive: Valproate
d. with psychological symptoms Oxcarbazepine Valproate Carbamazepine Children:
Topiramate Gabapentin Clobazam Oxcarbazepine
Zonisamide Gabapentin Carbamazepine
Phenytoin Lamotrigine Phenobarbital
Pregabalin Levetiracetam Phenytoin
Lacosamide Oxcarbazepine Topiramate
Ezogabine Valproate Valproate
Topiramate Vigabatrin
Elderly:
Gabapentin
Lamotrigine
Carbamazepine
2. Complex partial seizures (with Carbamazepine Lamotrigine Carbamazepine Adults:

impaired consciousness) Phenytoin Carbamazepine Lamotrigine Carbamazepine
a. simple partial onset followed by Valproate Levetiracetam Levetiracetam Levetiracetam
impaired consciousness Phenobarbital Oxcarbazepine Oxcarbazepine Phenytoin
b. impaired consciousness at onset Lamotrigine Alternatives: Valproate Zonisamide
Gabapentin Topiramate Adjunctive: Valproate
Oxcarbazepine Valproate Carbamazepine Children:
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16: Levetiracetam, Zonisamide Gabapentin Page 1 / 34
Carbamazepine
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a. simple partial onset followed by Valproate Levetiracetam Levetiracetam Levetiracetam
impaired consciousness Phenobarbital Oxcarbazepine Oxcarbazepine Phenytoin
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b. impaired consciousness at onset Lamotrigine Alternatives: Valproate Zonisamide
Elderly:
Gabapentin
Lamotrigine
Carbamazepine
3. Partial seizures evolving into Carbamazepine Lamotrigine Carbamazepine Adults:

secondary generalized seizures Phenytoin Carbamazepine Lamotrigine Carbamazepine
Valproate Levetiracetam Levetiracetam Levetiracetam
Phenobarbital Oxcarbazepine Oxcarbazepine Phenytoin
Lamotrigine Alternatives: Valproate Zonisamide
Elderly:
Gabapentin
Lamotrigine
Carbamazepine
Generalized seizures 1. Absence seizuresb (typical or Children:c Ethosuximide Ethosuximide Children:

(convulsive or atypical; also known as petite mal Ethosuximide Valproate Lamotrigine Ethosuximide
nonconvulsive) seizures) Valproate Alternatives: Valproate Valproate
Lamotrigine Lamotrigine Adjunctive: Lamotrigine

Clonazepam Ethosuximide
Zonisamide Lamotrigine
Levetiracetam Valproate
2. Tonicclonic seizures (also known as Carbamazepine Valproate Carbamazepine Adults:

grand mal seizures) Phenytoin Lamotrigine Lamotrigine Carbamazepine
Valproate Levetiracetam Oxcarbazepine Lamotrigine
Phenobarbital Alternatives: Valproate Oxcarbazepine
Lamotrigine Topiramate Adjunctive: Phenobarbital
Oxcarbazepine Zonisamide Clobazam Phenytoin
Topiramate Phenytoin Lamotrigine Topiramate
Levetiracetam Valproate
Valproate Gabapentin
Topiramate Levetiracetam
Vigabatrin
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16: Levetiracetam, Page 2 / 34
Carbamazepine
Phenobarbital
Phenytoin
Oxcarbazepine Zonisamide Clobazam Phenytoin
Topiramate Phenytoin Lamotrigine SAUDITopiramate
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Levetiracetam Access Provided
Valproate
by:
Valproate Gabapentin
Topiramate Levetiracetam
Vigabatrin
Children:
Carbamazepine
Phenobarbital
Phenytoin
Topiramate
Valproate
Oxcarbazepine
aOnly two highest available levels of evidence listed.
b Recent literature suggests either ethosuximide or valproic acid is a superior initial therapy compared to lamotrigine for absence seizures.5,6
cLamotrigine added to previous recommendation per expert panel.
Abbreviations: ANN, American Academy of Neurology; AES, American Epilepsy Society; NICE, UK National Institute for Clinical Excellence; ILAE, International League
Against Epilepsy.
THERAPEUTIC AND TOXIC CONCENTRATIONS
Like many of the newer antiepileptic drugs, the therapeutic range of levetiracetam is not well defined.9,10, and 11 However, levetiracetam serum
concentration measurement can be a useful adjunct in addition to monitoring treatment for therapeutic response and adverse effects. The therapeutic
range for epilepsy used by many laboratories for levetiracetam is 1246 μg/mL, and predose steadystate trough concentrations are usually obtained
for levetiracetam measurement. Some patients will experience a higher incidence of adverse effects in the upper end of these levels, so the efficacy of
lower serum concentrations should be assessed before moving to higher concentrations. The most common concentrationdependent side effects of
levetiracetam are sedation and behavioral disturbances.6
CLINICAL MONITORING PARAMETERS
The goals of therapy with anticonvulsants are to reduce seizure frequency and to maximize quality of life with a minimum of adverse drug effects.6
While it is desirable to entirely abolish all seizure episodes, it may not be possible to accomplish this in many patients. Patients should be monitored
for concentrationrelated side effects (sedation, behavioral disturbances). Somnolence, asthenia, and dizziness in adults and fatigue, aggression
anorexia, and irritability in children are also common adverse events. Serious side effects include psychotic episodes (hallucinations, unusual
behavior), mood changes (anxiety, depression, aggression, hostility), suicidal behavior, and muscle incoordination. StevensJohnson syndrome and
toxic epidermal necrolysis have both been reported during levetiracetam therapy. Generally, these adverse effects occurred within 1417 days of
starting treatment, although some cases have happened as late as 4 months after beginning treatment. Should either of these dermatologic reactions
develop, levetiracetam should be immediately discontinued and not restarted.6,12
Because epilepsy is an episodic disease state, patients do not experience seizures continuously. Thus, during dosage titration it is difficult to tell if the
patient is responding to drug therapy or simply is not experiencing any abnormal central nervous system discharges at that time. Levetiracetam doses
should be carefully titrated to individual patient response and tolerability. Steadystate serum concentrations of levetiracetam can be measured in
patients as an adjunct to therapy.10,11,13,14, and 15 Concentration monitoring is particularly useful if a therapeutic level has been established for a patient
and a new clinical event (drug interaction, new disease state or condition, etc) changes the pharmacokinetics of the drug. Levetiracetam
concentrations can also be measured to document patient adherence to drug treatment or when a patient is switched among the various dosage forms
(immediaterelease tablets, extendedrelease tablets, oral solution, or intravenous injection) to assure therapeutic levels are maintained.
BASIC CLINICAL PHARMACOKINETIC PARAMETERS

With normal renal function, levetiracetam is eliminated primarily as unchanged drug in the urine (∼65% of administered dose, Table 162). The
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a pharmacologically inactive metabolite and then eliminated into the urine (UBC L057, ∼20% of dose).
There are several other minor metabolites without antiseizure activity that account for the remainder of the dose. Metabolism of levetiracetam does
not seem to be conducted principally by the cytochrome P450 enzymes or the uridine 5′diphosphoglucuronosyltransferase (UGT) systems. Enzymatic
hydrolysis via type B esterases is a likely pathway for metabolite formation. The clearance, volume of distribution, and halflife for intravenous
concentrations can also be measured to document patient adherence to drug treatment or when a patient is switched among the various dosage forms
(immediaterelease tablets, extendedrelease tablets, oral solution, or intravenous injection) to assure therapeutic levels areSAUDI DIGITAL LIBRARY
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BASIC CLINICAL PHARMACOKINETIC PARAMETERS

With normal renal function, levetiracetam is eliminated primarily as unchanged drug in the urine (∼65% of administered dose, Table 162). The
remainder of the drug is largely converted to a pharmacologically inactive metabolite and then eliminated into the urine (UBC L057, ∼20% of dose).
There are several other minor metabolites without antiseizure activity that account for the remainder of the dose. Metabolism of levetiracetam does
not seem to be conducted principally by the cytochrome P450 enzymes or the uridine 5′diphosphoglucuronosyltransferase (UGT) systems. Enzymatic
hydrolysis via type B esterases is a likely pathway for metabolite formation. The clearance, volume of distribution, and halflife for intravenous
levetiracetam average about 0.95 mL/min/kg, 0.6 L/kg, and 7.3 hours, respectively. Levetiracetam follows linear pharmacokinetics within the usual
dosage range.3,9,16,17,18, and 19
TABLE 162
Disease States and Conditions That Alter Levetiracetam Pharmacokinetics
Disease
Cl/F V/F t1/2 Comment
State/Condition
Adult, normal kidney and 0.9 0.6 7.6 h Levetiracetam is primarily eliminated by the kidneys as unchanged drug (∼65% of dose).
liver function, mL/min/kg L/kg 7.3 h UCB L057, the primary metabolite, is also eliminated in the urine (∼20% of dose). Tmax
immediaterelease oral 0.89 0.57 6.7 h averages 0.8 h for the oral solution and 1.5 h for the immediate release tablets. Oral
dosage forms mL/min/kg L/kg 7.3 h bioavailability is 92% compared to intravenous drug. The steadystate peaktrough ratio
0.92 N/A 7.4 h is 0.94 for immediaterelease tablets. The overall mean pharmacokinetic values are: Cl/F
mL/min/kg 0.57 7.2 h = 0.90 mL/min/kg, V/F = 0.56 L/kg, t1/2 = 7.3 h
0.93 L/kg
mL/min/kg 0.54
0.85 L/kg
mL/min/kg 0.52
0.85 L/kg
mL/min/kg
Adult, normal kidney and 0.90 0.56 7.3 h T max at steadystate equal to 4.5 h. Steadystate peaktrough ratio for extendedrelease
liver function, extended mL/min/kg L/kg tablet (1.19) given once daily similar to immediaterelease (1.27) given twice daily.
release tablet Bioavailability of extendedrelease tablet similar to immediaterelease tablet.
Adult, variable renal N/A N/A To determine Cl/F for patient with decreased renal function, multiply the Cl/F value by
function, normal liver percentage.
function
Adult, endstage renal 18.2 0.5 24.6 h Hemodialysis clearances for levetiracetam and UCB L057 metabolite are 127 mL/min/1.73
disease, normal liver mL/min/1.73 L/kg m2 and 99 mL/min/1.73 m2, respectively. About ½ of levetiracetam is removed by 4 h
function m2 hemodialysis with lowflux filter.
Adult, variable renal Healthy 47.3 L 7.6 h Severe liver disease group had lower renal function (63 mL/min/1.73 m2 vs 100121
function, liver disease control: 49.1 L 7.6 h
mL/min/1.73 m2 for other groups) and lower nonrenal Cl/F (12.4 mL/min/1.73 m2 vs 19
64.3 48.6 L 8.7 h
21 mL/min/1.73 m2 for the other groups). Decreased Cl/F and prolonged t1/2 for severe
mL/min/1.73 44.6 L 18.4 h
liver function group is due to both decreased renal and liver elimination.
m2
Mild liver
disease:
62.5
mL/min/1.73
m2
Moderate
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mL/min/1.73
2
Mild liver
disease: SAUDI DIGITAL LIBRARY
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mL/min/1.73
m2
Moderate
liver disease:
55.4
mL/min/1.73
m2
Severe liver
disease:
29.2
mL/min/1.73
m2
Adult, normal kidney and N/A 7.4 h Inducer AED increase the Cl/F and decrease the t1/2 of levetiracetam. VPA decreases the
liver function, variable 0.6 6.1 h Cl/F and increases the t1/2 of levetiracetam. Administration of VPA with one or more
concurrent AED therapy L/kg 11.5 h
inducer AED attenuates the changes.
N/A 9.4 h
N/A
Adult, elderly, variable N/A N/A Elderly patients have lower Cl/F compared to younger patients. Inducer AED increase
concurrent other AED N/A N/A Cl/F in both patient groups.
therapy N/A N/A
Adult, very elderly, N/A N/A Very elderly and elderly patients both have lower Cl/F values than younger adults for
variable concurrent N/A N/A levetiracetam monotherapy. The oldest patients have the lowest overall Cl/F. Inducer
other AED therapy AED increase Cl/F across the board and bring parity to Cl/F to the elderly groups.
Adult, normal kidney and 0.92 0.56 7.2 h By definition, F = 1 for intravenous levetiracetam. Therefore, shown values are for Cl and
liver function, mL/min/kg L/kg 8.3 h V, not the hybrid constants. The overall mean pharmacokinetic values for intravenous
intravenous drug 0.97 0.66 drug are: Cl = 0.95 mL/min/kg, V = 0.6 L/kg, t1/2 = 7.8 h
mL/min/kg L/kg
Adult, normal kidney and 1.09 0.43 5.2 h Clearance was higher in neurologic critical care patients with head trauma. By definition,
liver function, neurologic mL/min/kg L/kg F = 1 for intravenous levetiracetam. Therefore, shown values are for Cl and V, not the
critical care, intravenous hybrid constants. V was calculated as Vss, which computationally is smaller than V
drug calculated using the area method.
Adult, normal kidney and 0.91 0.72 9.4 h Bioavailability for intramuscular injection was 100% compared to intravenous drug. Tmax
liver function, mL/min/kg L/kg = 3.1 h.
intramuscular
administration
Adult females, normal Baseline N/A N/A Levetiracetam steadystate levels decline during the first and second trimesters, but
kidney and liver function, (before N/A N/A decrease precipitously in the third trimester. Umbilical cord/mother serum
pregnant pregnancy concentration ratio = 1.09. Breast milk/mother serum concentration ratio = 1.05.
or >1 mo
after
delivery):
125 L/d
Third
trimester:
427 L/d
Neonates, 3741 wks
16: Levetiracetam, Single dose, 0.89 8.9 h Cl/F rapidly changes after birth. V/F is larger for neonates, which is similar to many Page
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longer for neonates than children and adults.
kgweight, single dose of age 2 d: N/A 9.1 h
intravenous PB 20 mg/kg 1.21 N/A
delivery):
125 L/d
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Third
trimester:
427 L/d
Neonates, 3741 wks Single dose, 0.89 8.9 h Cl/F rapidly changes after birth. V/F is larger for neonates, which is similar to many other
gestational age, 2.553.70 postnatal L/kg 18.5 h drugs. t1/2 is longer for neonates than children and adults.
kgweight, single dose of age 2 d: N/A 9.1 h
intravenous PB 20 mg/kg 1.21 N/A
given before mL/min/kg
levetiracetam Multiple
dose for 7 d
after birth:
Day 1, 0.71
mL/min/kg
Day 7, 1.31
mL/min/kg
Pediatric patients, Age 2.346.2 0.63 5.3 h Generally, children taking inducer AED have higher Cl/F and V/F compared to adults. t1/2
normal kidney and liver mo, mixed L/kg 6.0 h values are shorter.
function, variable AED usage: 0.72 4.4 h
concurrent other AED 1.46 L/kg 5.2 h
therapy mL/min/kg N/A
Age 612 y, N/A
mixed AED
usage:
1.43
mL/min/kg
Age 412 y
old:
w/CBZ, 1.23
mL/min/kg
w/VPA, 1.08
mL/min/kg
Abbreviations: AED, antiepileptic drug; PHT, phenytoin; CBZ, carbamazepine; OXC, oxcarbazepine; PB, phenobarbital; PRIM, primidone; VPA, valproic acid.
Levetiracetam is available in a variety of immediaterelease tablets (tablets: 250 mg, 500 mg, 750 mg, 1000 mg) and as extendedrelease tablets (500 mg,
750 mg). An oral solution (100 mg/mL) and intravenous injection (500 mg/5 mL) are also available for administration. Bioavailability is ∼92% for the
various oral dosage forms, and if the intravenous injection is given intramuscularly, the bioavailability is 100%. Food intake does not appear to alter
bioavailability for the oral dosage forms.20,21
For single doses, peak concentrations occur sooner (Tmax) for the oral solution (∼0.8 hours) compared to the immediaterelease tablets (∼1.5
hours).17,22,23,24, and 25 For multiple doses of the extendedrelease dosage form administered twice daily, Tmax occurs at about 4.5 hours. The steady
state maximumtominimum concentration ratio is 1.27 for immediaterelease tablets given every 12 hours compared to 1.19 for extendedrelease
tablets given once daily.26 When patients are switched between dosage forms, they should be closely monitored for changes in efficacy or toxicity, and
measurement of levetiracetam serum concentrations should be considered before and after the change has been made.
The plasma protein binding of levetiracetam is <10%.17,18, and 19 Levetiracetam crosses the placental barrier, and at birth the umbilical cord blood to
maternal serum concentration ratio is approximately 1.09. Levetiracetam also crosses into the breast milk of lactating mothers with a breast milkto
maternal serum ratio of 1.05. After breastfeeding from mothers taking levetiracetam, the resulting range of levetiracetam serum concentration in
newborns was 0.73.4 μg/mL.13 The range of mean levetiracetam saliva to serum ratios in patients measured during multiple dosing is 0.360.41, and
the correlation coefficient for concentrations in the two fluids is 0.860.87.27
EFFECTS
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Most investigations with levetiracetam have been conducted with oral dosage forms, so pharmacokinetic results are usually expressed as hybrid
The plasma protein binding of levetiracetam is <10%.17,18, and 19 Levetiracetam crosses the placental barrier, and at birth the umbilical cord blood
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maternal serum concentration ratio is approximately 1.09. Levetiracetam also crosses into the breast milk of lactating mothers with
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maternal serum ratio of 1.05. After breastfeeding from mothers taking levetiracetam, the resulting range of levetiracetam serum concentration in
newborns was 0.73.4 μg/mL.13 The range of mean levetiracetam saliva to serum ratios in patients measured during multiple dosing is 0.360.41, and
the correlation coefficient for concentrations in the two fluids is 0.860.87.27
EFFECTS OF DISEASES AND CONDITIONS ON PHARMACOKINETICS AND DOSING

Most investigations with levetiracetam have been conducted with oral dosage forms, so pharmacokinetic results are usually expressed as hybrid
constants that include bioavailability (F) for clearance (Cl/F) and volume of distribution (V/F) as single values (see Table 162). Adults with normal liver
and kidney function that take no hepatic enzyme inducers or inhibitors have an average halflife of 7.3 hours, a mean Cl/F equal to 0.90 mL/min/kg,
and an average V/F of 0.56 L/kg for levetiracetam (see Table 162).19,22,23,24, and 25 The clearance, volume of distribution, and halflife for intravenous
levetiracetam average about 0.95 mL/min/kg, 0.6 L/kg, and 7.3 hours, respectively.20,21 Because plasma protein binding is very low (<10%), it is not
altered by any disease states or conditions that alter levetiracetam pharmacokinetics, and volume of distribution is similar for most patient categories.
The majority of a levetiracetam dose (∼65%) is eliminated unchanged in the urine. Because of this, renal disease prolongs levetiracetam halflife and
decreases levetiracetam clearance in a graded manner according to the degree of renal damage observed in the patient. Compared to adults with
normal renal function, patients with a creatinine clearance (CrCl) of 5080 mL/min have 60% of the normal Cl/F. Similarly, patients with CrCl equal to
3050 mL/min have 50% of the normal Cl/F and patients with CrCl <30 mL/min have 40% of the normal Cl/F. Patients with endstage renal disease have
a levetiracetam clearance of 18.2 mL/min/1.73 m2, a volume of distribution equal to 0.5 L/kg, and a halflife of 24.6 hours. The hemodialysis clearances
for levetiracetam and UCB L057 (the major metabolite) are 127 mL/min/1.73 m2 and 99 mL/min/1.73 m2, respectively. During a 4hour hemodialysis
session with a lowflux filter, about onehalf of levetiracetam is removed from the body.28,29 For patients with renal dysfunction, levetiracetam doses
should be titrated to clinical response, and measurement of levetiracetam serum concentrations can be a helpful adjunct. Due to the variability in the
pharmacokinetics for levetiracetam, patients with renal disease should be closely monitored for adverse effects due to levetiracetam therapy.
Since only a moderate amount of levetiracetam is eliminated by metabolic conversion (∼35%) and the liver is not the principal site of metabolism, there
is only a modest change in levetiracetam pharmacokinetics for subjects with hepatic disease. An index of liver dysfunction can be gained by applying
the ChildPugh clinical classification system to the patient (Table 163).30 ChildPugh scores are completely discussed in Chapter 3 (Drug Dosing in
Special Populations: Renal and Hepatic Disease, Dialysis, Heart Failure, Obesity, and Drug Interactions), but will be briefly discussed here. The Child
Pugh score consists of five laboratory tests or clinical symptoms: serum albumin, total bilirubin, prothrombin time, ascites, and hepatic
encephalopathy. Each of these areas is given a score of 1 (normal) to 3 (severely abnormal; see Table 163), and the scores for the five areas are
summed. The ChildPugh score for a patient with normal liver function is 5 while the score for a patient with grossly abnormal serum albumin, total
bilirubin, and prothrombin time values in addition to severe ascites and hepatic encephalopathy is 15. The pharmacokinetic changes for levetiracetam
range from modest ones (mild liver disease: none; moderate liver disease: halflife = 8.7 hours, Cl/F = 55.4 mL/min/1.73 m2, V/F = 48.6 L) for patients
with moderate liver disease (ChildPugh score = 79 points) to larger ones (halflife = 18.4 hours, Cl/F = 29.2 mL/min/1.73 m2) for patients with severe
liver disease (ChildPugh score = 1015 points). Unfortunately, the patients with severe liver disease included in the research study also had decreased
renal function compared to the other liver disease groups, so it is difficult to assign the entire change in levetiracetam pharmacokinetics to hepatic
dysfunction. Generally, no change in dose is needed for patients with mildmoderate liver disease. But, for patients with severe liver disease (especially
with a concurrent decline in renal function), an initial dosage decrease of 50% is recommended as a prudent change.31 Doses of levetiracetam for liver
disease patients should be titrated to clinical response, and measurement of serum concentrations can be a helpful adjunct. Because there is
variability in the pharmacokinetics for the agent, patients with liver disease should be closely monitored for adverse effects due to levetiracetam
therapy.
TABLE 133
ChildPugh Scores for Patients With Liver Disease
Test/Symptom Score 1 Point Score 2 Points Score 3 Points
Total bilirubin (mg/dL) <2.0 2.03.0 >3.0
Serum albumin (g/dL) >3.5 2.83.5 <2.8
Prothrombin time (seconds prolonged over control) <4 46 >6

16: Levetiracetam,
Ascites Absent Slight Moderate Page 7 / 34
Hepatic encephalopathy None Moderate Severe
with a concurrent decline in renal function), an initial dosage decrease of 50% is recommended as a prudent change.31 Doses of levetiracetam for liver
disease patients should be titrated to clinical response, and measurement of serum concentrations can be a helpful adjunct. Because there is
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variability in the pharmacokinetics for the agent, patients with liver disease should be closely monitored for adverse effects due to levetiracetam
therapy.
TABLE 133
ChildPugh Scores for Patients With Liver Disease
Test/Symptom Score 1 Point Score 2 Points Score 3 Points
Total bilirubin (mg/dL) <2.0 2.03.0 >3.0
Serum albumin (g/dL) >3.5 2.83.5 <2.8
Prothrombin time (seconds prolonged over control) <4 46 >6
Ascites Absent Slight Moderate
Hepatic encephalopathy None Moderate Severe
ChildPugh Class A, mild liver disease: 56 points; ChildPugh Class B, moderate liver disease: 79 points; ChildPugh Class C, severe liver disease: 1015 points.
Adult and pediatric patients taking levetiracetam for the treatment of seizures have been studied while taking other antiepileptic drugs, and it is
important to take concurrent medications into account when interpreting the findings of pharmacokinetic studies (see Table 162). Because the
metabolism of levetiracetam does not include the cytochrome P450 system or the UGT enzymes, the induction (phenytoin, carbamazepine,
oxcarbazepine, phenobarbital, primidone) or inhibition (valproic acid and its derivatives) effects of other antiepileptics is moderated to a large extent
compared to other antiseizure medications. For adults, taking other antiepileptic drugs that are inducers simultaneously with levetiracetam will
increase Cl/F by about 15%30% and decrease halflife by about 16% for levetiracetam. By comparison, taking valproic acid or one of its derivatives that
are inhibitors concurrently with levetiracetam will decrease Cl/F by ∼22% and increase halflife by ∼58% for levetiracetam. When either inducers or
inhibitors are coadministered alone with levetiracetam, V/F for levetiracetam will remain unchanged with concomitant antiepileptic therapy. If
antiepileptic drugs from both the inducer and the inhibitor categories are given at the same time with levetiracetam, the effect on levetiracetam
pharmacokinetics are largely neutral (∼9% decrease in Cl/F, ∼29% increase in halflife).22,32 For the elderly and very elderly, the basic drug interaction
pattern for levetiracetam with other antiepileptic drugs is the same, but adult patients over the age of 64 years have lower baseline levetiracetam Cl/F
values for the effects to build upon.33,34
Pediatric patients taking other antiepileptic drugs that are inducers or inhibitors simultaneously with levetiracetam produces similar results for
levetiracetam pharmacokinetic parameters. The inducerclass antiseizure medications (phenytoin, carbamazepine, oxcarbazepine, phenobarbital,
primidone) increase Cl/F and decrease halflife for levetiracetam compared to patients taking levetiracetam monotherapy. The inhibitorclass
antiseizure medications (valproic acid and its derivatives) decrease Cl/F and increase halflife for levetiracetam compared to patients taking
levetiracetam monotherapy.35,36, and 37
Neonates (gestational age = 3741 weeks, birth weight = 25503700 g) have been treated with intravenous levetiracetam to control seizures after
delivery. Levetiracetam clearance on the first day of treatment was 0.71 mL/min/kg but rapidly increased over 7 days of therapy by 85%. During the
same period, halflife decreased by 51% (see Table 162).
Intravenous levetiracetam has been investigated in normal individuals and patients with head trauma who were admitted to a neurologic critical care
unit (see Table 162). Trauma patients are often hypermetabolic due to the physiologic demands placed on the body during the healing process. For
this case, levetiracetam clearance is about 15% higher and halflife is about 33% shorter than normal adults.20,21,38 If the intravenous dosage form is
administered intramuscularly to normal adults, Tmax averages 3.1 hours, and the bioavailability compared to intravenous drug is 100%.21
Using the FDA pregnancy classification system, levetiracetam is a Category C medication. Therefore, levetiracetam is used to treat pregnant women
when the potential benefits of drug therapy outweigh the potential risks. Pregnancy alters the Cl/F of levetiracetam (see Table 162). Compared to
baseline values, Cl/F continuously increases as the pregnancy progresses from the first to the second trimester, but a precipitous rise is noted during
the third trimester. Clearance remains elevated until delivery, then starts to decline. By 1 month postpartum, levetiracetam clearance returns to
baseline values. Levetiracetam crosses the placental barrier and is found in the breast milk of lactating mothers. At birth, the umbilical cord bloodto
maternal serum concentration ratio is approximately 1.09. The breast milktomaternal serum ratio is 1.05. After breastfeeding from mothers
16: Levetiracetam, taking
Page 8 / 34
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0.73.4 μg/mL. 13
DRUG INTERACTIONS
SAUDI
Using the FDA pregnancy classification system, levetiracetam is a Category C medication. Therefore, levetiracetam is used to treat DIGITAL
pregnant LIBRARY
women
when the potential benefits of drug therapy outweigh the potential risks. Pregnancy alters the Cl/F of levetiracetam (see TableAccess
162). Compared
Provided by: to
baseline values, Cl/F continuously increases as the pregnancy progresses from the first to the second trimester, but a precipitous rise is noted during
the third trimester. Clearance remains elevated until delivery, then starts to decline. By 1 month postpartum, levetiracetam clearance returns to
baseline values. Levetiracetam crosses the placental barrier and is found in the breast milk of lactating mothers. At birth, the umbilical cord bloodto
maternal serum concentration ratio is approximately 1.09. The breast milktomaternal serum ratio is 1.05. After breastfeeding from mothers taking
levetiracetam, the resulting range of levetiracetam serum concentration in newborns was 0.73.4 μg/mL.13
DRUG INTERACTIONS
Because the metabolism of levetiracetam does not involve the cytochrome P450 system or the UGT enzymes, the induction (phenytoin,
carbamazepine, oxcarbazepine, phenobarbital, primidone) or inhibition (valproic acid and its derivatives) effects of other antiepileptics on
levetiracetam pharmacokinetics is moderate. Adult and pediatric patients taking levetiracetam for the treatment of seizures have been studied while
taking other antiepileptic drugs, and it is important to take the effect of newly prescribed medications on levetiracetam pharmacokinetics into account
when assessing a patient’s therapy (see Table 162).22,32,33, and 34 When other antiepileptic drugs are added to the treatment regimen of patients taking
levetiracetam, patients should be monitored to ensure therapeutic effects are achieved and new adverse effects do not occur. Also, the effects of
adding other common hepatic enzyme inducers or inhibitors to the therapeutic regimen of patients taking levetiracetam have not been thoroughly
assessed. Measurement of levetiracetam steadystate concentrations can be a helpful adjunct when considering the effect of new therapies added to
the medication regimen of epileptic patients.
INITIAL DOSAGE DETERMINATION METHODS

Several methods to initiate levetiracetam therapy are available. The Pharmacokinetic Dosing method is the most flexible of the techniques. It allows
individualized target serum concentrations to be chosen for a patient, and each pharmacokinetic parameter can be customized to reflect specific
disease states and conditions present in the patient. Literaturebased recommended dosing is a very commonly used method to prescribe initial doses
of levetiracetam. Doses are based on those that commonly produce steadystate concentrations in the lower end of the therapeutic range, although
there is a wide variation in the actual concentrations for a specific patient (see Table 162).
Pharmacokinetic Dosing Method
The goal of initial dosing of levetiracetam is to compute the best dose possible for the patient given their set of disease states and conditions that
influence levetiracetam pharmacokinetics and the epileptic disorder being treated. In order to do this, pharmacokinetic parameters for the patient will
be estimated using average parameters measured in other patients with similar disease state and condition profiles.
Clearance, Volume of Distribution, and HalfLife Estimates
Levetiracetam is predominately eliminated unchanged by the kidney. Serum creatinine (SCr) and estimated creatinine clearance (CrClest) are used to
estimate the elimination of agents that are renally eliminated, and there is a good correlation between creatinine clearance and levetiracetam
clearance.29,39,40, and 41 Unfortunately, the exact equation that best describes the relationship between CrClest and levetiracetam clearance (Cl/F for
orally administered drug, Cl for intravenously or intramuscularly administered drug) remains unpublished. Instead, clearance adjustments are used to
account for decreased elimination for various CrClest brackets (see Table 162). Because of this, a patient is categorized according to the disease states
and conditions that are known to change levetiracetam clearance, and the clearance previously measured in these studies is used as an estimate of the
current patient’s levetiracetam clearance rate (see Table 162). Then, if the patient has a CrCl ≤80 mL/min, the clearance is adjusted for decreased renal
function. For example, an adult epileptic patient with normal liver function that is to be initially treated with oral levetiracetam monotherapy (no other
antiepileptic drug administration) would be assigned a levetiracetam Cl/F value equal to 0.90 mL/min/kg, a V/F value of 0.56 L/kg, and a t1/2 = 7.3 h.
If the patient has an estimated CrCl >80 mL/min, these estimates are used to compute levetiracetam dosages. If the patient has an estimated CrCl ≤80
mL/min, the clearance is adjusted for their renal function. To extend the current example, if the patient had a CrCl = 40 mL/min, the Cl/F value would be
adjusted to 0.45 mL/min/kg (Cl/F = 0.50 • 0.90 mL/min/kg = 0.45 mL/min/kg), and the t1/2 value would be adjusted to 14.4 hours (t1/2 =
[0.693(V/F)]/(Cl/F) = [0.693(0.56 L/kg)(1000 mL/L)]/[(0.45 mL/min/kg)(60 min/h)] = 14.4 h, where 1000 mL/L and 60 min/h are unit conversion factors). If
the patient is receiving intravenous or intramuscular levetiracetam (F = 1), the same type of adjustment for renal function is made using Cl instead of
Cl/F.
Selection of Appropriate Pharmacokinetic Model and Equations

When
©2024oral therapy
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Hill. All Rightslevetiracetam is usually
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These dosage intervals provide a relatively smooth serum concentrationtime curve that approximates an intravenous infusion. Because of this
concentrationtime profile, a very simple pharmacokinetic equation that calculates the average levetiracetam steadystate concentration (Css in μg/mL
adjusted to 0.45 mL/min/kg (Cl/F = 0.50 • 0.90 mL/min/kg = 0.45 mL/min/kg), and the t1/2 value would be adjusted to 14.4 hours (t1/2 =
[0.693(V/F)]/(Cl/F) = [0.693(0.56 L/kg)(1000 mL/L)]/[(0.45 mL/min/kg)(60 min/h)] = 14.4 h, where 1000 mL/L and 60 min/h are unit conversion factors). If
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the patient is receiving intravenous or intramuscular levetiracetam (F = 1), the same type of adjustment for renal function is made using Cl instead of
Cl/F.
When oral therapy is required, levetiracetam is usually given once daily for extendedrelease tablets or twice daily for the other oral dosage forms.
concentrationtime profile, a very simple pharmacokinetic equation that calculates the average levetiracetam steadystate concentration (Css in μg/mL
= mg/L) is widely used and allows maintenance dose computation: Css = (D/τ)/(Cl/F) or D = Css(Cl/F)τ, where D is the dose of levetiracetam in mg, Cl/F is
the levetiracetam hybrid clearance/bioavailability parameter in L/h, and τ is the dosage interval in hours.
If intravenous dosing is needed, levetiracetam is usually given twice daily as a 15minute infusion. For this route of administration, a predose steady
state trough concentration (Cssmin) is usually maintained in the desired concentration range: Cssmin = (De−kτ)/[V(1 − e−kτ)] or D = [Cssmin V(1 − e−kτ)]/(e
−kτ), where D is the dose of levetiracetam in mg, V is the volume of distribution in L, k is the elimination rate constant in h−1 [k = (0.693)/(t
1/2)], and τ is
the dosage interval in hours.
Example 1
KL is a 50yearold, 70kg (height = 5 ft 10 in) male with complex partial seizures who requires therapy with levetiracetam. His serum creatinine
equals 0.9 mg/dL. He has a normal liver function and is currently taking carbamazepine (steadystate concentration = 9.2 μg/mL). Additional dosage
increases have been tried with carbamazepine, but they have been unsuccessful due to development of adverse effects. Suggest an initial
levetiracetam dosage regimen using immediaterelease tablets designed to achieve a steadystate levetiracetam concentration equal to 15 μg/mL.
1. Estimate creatinine clearance.
This patient has a stable serum creatinine and is not obese. The CockcroftGault equation can be used to estimate creatinine clearance:
This patient has a CrClest >80 mL/min, so levetiracetam clearance will not need to be adjusted for renal function (see Table 162).
2. Estimate clearance, volume of distribution, and halflife according to disease states and conditions present in the patient.
The Cl/F rate for a patient taking carbamazepine is 1.17 mL/min/kg: Cl/F = (1.17 mL/min/kg)70 kg = 81.9 mL/min. The estimated V/F would be 0.6
L/kg, and the estimated halflife equals 6.1 h.
3. Compute dosage regimen.
Levetiracetam immediaterelease tablets will be prescribed to this patient. (Note: μg/mL = mg/L and this concentration unit was substituted for
Css in the calculations so that unnecessary unit conversion was not required.) The dosage equation for oral levetiracetam is: D = Css(Cl/F)τ = (15
mg/L • 81.9 mL/min • 12 h • 60 min/h)/(1000 mL/L) = 885 mg, rounded to 1000 mg every 12 hours.
A steadystate trough levetiracetam serum concentration can be measured after steadystate is attained in 35 halflives. Since the patient is
expected to have a halflife equal to 6.1 hours, the levetiracetam steadystate concentration could be obtained any time after the second day of
dosing (5 halflives = 5 • 6.1 h = 31 h or 1.3 d). Levetiracetam serum concentrations should also be measured if the patient experiences an
exacerbation of their epilepsy or if the patient develops potential signs or symptoms of levetiracetam toxicity.
Example 2
Same patient profile as in example 1, but serum creatinine is 1.8 mg/dL indicating renal impairment.
Downloaded 202443
This patient 9:49estP= 3050
has a CrCl Your IP is 154.59.124.91
mL/min, so levetiracetam clearance will be adjusted for renal function by multiplying Cl/F by 0.50 (see Table 16
©20242).McGraw Hill. All Rights Reserved. Terms of Use • Privacy Policy • Notice • Accessibility
dosing (5 halflives = 5 • 6.1 h = 31 h or 1.3 d). Levetiracetam serum concentrations should also be measured if the patientSAUDI DIGITAL
experiences an LIBRARY
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Example 2
This patient has a CrClest = 3050 mL/min, so levetiracetam clearance will be adjusted for renal function by multiplying Cl/F by 0.50 (see Table 16
2).
The Cl/F rate for a patient taking carbamazepine is 1.17 mL/min/kg, and the adjustment for renal dysfunction is 0.50: Cl/F = (0.50)1.17 mL/min/kg
= 0.59 mL/min/kg: Cl/F = (0.59 mL/min/kg)70 kg = 41.3 mL/min. The estimated V/F would be 0.6 L/kg, and the estimated halflife equals: t1/2 =
[0.693(V/F)]/(Cl/F) = [0.693(0.6 L/kg)(1000 mL/L)]/[(0.59 mL/min/kg)(60 min/h)] = 11.7 h
expected to have a halflife equal to 11.7 hours, the levetiracetam steadystate concentration could be obtained any time after the third day of
Example 3
Same patient profile as in example 1, but patient not taking carbamazepine, and he will receive an intravenous levetiracetam dosage regimen
designed to achieve a steadystate trough concentration equal to 15 μg/mL.
This patient has a CrClest > 80 mL/min, so levetiracetam clearance will not need to be adjusted for renal function (see Table 162).
The Cl for a patient taking intravenous levetiracetam as monotherapy is 0.95 mL/min/kg: Cl = (0.95 mL/min/kg) 70 kg = 66.5 mL/min. The
estimated V would be 0.6 L/kg: V = (0.6 L/kg)70 kg = 42 L. The estimated halflife equals 7.8 h, so k = (0.693)/(t1/2) = (0.693)/(7.8 h) = 0.089 h−1.
Levetiracetam intravenous injection will be prescribed to this patient. (Note: μg/mL = mg/L and this concentration unit was substituted for Css in
the calculations so that unnecessary unit conversion was not required.) The dosage equation for intravenous levetiracetam is: D = [Cssmin V(1 − e
−kτ)]/(e−kτ) = [15 mg/L • 42 L (1 − e−(0.089h−1)(12 h))]/(e−(0.089h−1)(12 h)) = 1203 mg, rounded to 1250 mg every 12 hours.
A steadystate
Downloaded trough
202443 levetiracetam
9:49 P Your IP isserum concentration can be measured after steadystate is attained in 35 halflives. Since the patient is
154.59.124.91
16: Levetiracetam,
expected to have a halflife equal to 7.8 hours, the levetiracetam steadystate concentration could be obtained any time after the second Page 11of
day / 34
SAUDI
dosing (5 halflives = 5 • 11.7 h = 59 h or 2.5 d). Levetiracetam serum concentrations should also be measured if the patient DIGITALanLIBRARY
experiences
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Example 3
The Cl for a patient taking intravenous levetiracetam as monotherapy is 0.95 mL/min/kg: Cl = (0.95 mL/min/kg) 70 kg = 66.5 mL/min. The
estimated V would be 0.6 L/kg: V = (0.6 L/kg)70 kg = 42 L. The estimated halflife equals 7.8 h, so k = (0.693)/(t1/2) = (0.693)/(7.8 h) = 0.089 h−1.
Levetiracetam intravenous injection will be prescribed to this patient. (Note: μg/mL = mg/L and this concentration unit was substituted for Css in
the calculations so that unnecessary unit conversion was not required.) The dosage equation for intravenous levetiracetam is: D = [Cssmin V(1 − e
−kτ)]/(e−kτ) = [15 mg/L • 42 L (1 − e−(0.089h−1)(12 h))]/(e−(0.089h−1)(12 h)) = 1203 mg, rounded to 1250 mg every 12 hours.
LiteratureBased Recommended Dosing
Because of the large amount of variability in levetiracetam pharmacokinetics, even when concurrent disease states and conditions are identified, most
clinicians believe that the use of standard drug doses for various situations is warranted. The original computation of these doses were based on the
Pharmacokinetic Dosing method, and subsequently modified based on clinical experience. In general, the expected steadystate serum concentrations
used to compute these doses was in the lower end of the therapeutic range (1215 μg/mL). For adults, the initial dose of levetiracetam is 1000 mg/d,
administered once daily for the extendedrelease tablet and as divided doses every 12 hours for the other oral dosage forms. The dose is titrated up
1000 mg/d every 2 weeks as needed, and the patient is monitored for seizure frequency and adverse drug effects. The maximum dose is usually 3000
4000 mg/d. Because the majority of levetiracetam is eliminated unchanged in the urine, doses are adjusted for renal dysfunction (Table 164). If the
patient has severe hepatic dysfunction (ChildPugh score ≥10), the prescribed maintenance dose can be decreased by 50%. For children, the dose
varies according to age, and Table 165 lists initial doses, dosage increases during the titration period, and the maximum recommended dose.42
TABLE 164
LiteratureBased Doses for Levetiracetam in Adult Patients With Renal Dysfunction
C r C le s t (mL/min/1.73 m2 ) Dose
>80 5001500 mg every 12 h
5080 5001000 mg every 12 h
3050 250750 mg every 12 h

16: Levetiracetam,
<30 250500 mg every 12 h
Page 12 / 34
1000 mg/d every 2 weeks as needed, and the patient is monitored for seizure frequency and adverse drug effects. The maximum dose is usually 3000
4000 mg/d. Because the majority of levetiracetam is eliminated unchanged in the urine, doses are adjusted for renal dysfunction (Table 164). If the
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patient has severe hepatic dysfunction (ChildPugh score ≥10), the prescribed maintenance dose can be decreased by 50%. For children, the dose
varies according to age, and Table 165 lists initial doses, dosage increases during the titration period, and the maximum recommended dose.42
TABLE 164
LiteratureBased Doses for Levetiracetam in Adult Patients With Renal Dysfunction
C r C le s t (mL/min/1.73 m2 ) Dose
>80 5001500 mg every 12 h
5080 5001000 mg every 12 h
3050 250750 mg every 12 h
<30 250500 mg every 12 h
Endstage renal disease patients receiving hemodialysis: 5001000 mg every 24 h maintenance dose, with a replacement supplemental dose of 250500 mg after a
dialysis session.
To normalize CrClest (in mL/min) to a standard body surface area of 1.73 m2 (mL/min/1.73 m2), first compute the patient’s own body surface area (BSA in m2): BSA =
0.007184 • W0.425 • H0.725, where W is weight in kg and H is height in cm.46 Then, apply the normalization equation: CrClest (in mL/min/1.73 m2) = (CrClest/BSA)1.73 m2.
Example: For a patient with a height = 173 cm, weight = 67 kg, CrClest = 65 mL/min: BSA = 0.007184 • W0.425 • H0.725 = 0.007184 • (67 kg)0.425 • (173 cm)0.725 = 1.80 m2,
CrClest (in mL/min/1.73 m2) = [(CrClest)/(BSA)]1.73 m2 = [(65 mL/min)/(1.80 m2)]1.73 m2 = 62.5 mL/min/1.73 m2.
TABLE 165
LiteratureBased Initial Dose, Titration Rate, and Maximum Dose for Levetiracetam ImmediateRelease Dosage Forms in Children
Initial Dose Additional Titration Dose (mg/kg/d, Given Every 12 hours. This Maximum Dose(mg/kg/d, Given
Age
(mg/kg/d, Given Dose is Added to Current Maintenance Dose Every 2 weeks, Based Every 12 hours, Based on
Group
Every 12 hours) on Response and Adverse Effects) Response and Adverse Effects)
16 mo 14 14 42
6 mo 20 20 50
to 4 y
416 y 20 20 60
To illustrate the similarities and differences between this method of dosage calculation and the Pharmacokinetic Dosing method, the same examples
used in the previous section will be used.
Example 4
equals 0.9 mg/dL. He has normal liver function and is currently taking carbamazepine (steadystate concentration = 9.2 μg/mL). Additional dosage
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To illustrate the similarities and differences between this method of dosage calculation and the Pharmacokinetic Dosing method, the same examples
used in the previous section will be used.
Example 4
2. Estimate levetiracetam dose according to disease states and conditions present in the patient.
For adults, the initial dose of levetiracetam is 1000 mg/d, administered as divided doses every 12 hours for immediaterelease tablets. The dose
is titrated up 1000 mg/d every 2 weeks as needed, and the patient is monitored for seizure frequency and adverse drug effects. The maximum
dose is usually 30004000 mg/d.
Example 5
This patient has a CrClest between 30 and 50 mL/min, so levetiracetam clearance will be adjusted for renal function according to the
recommendations in Table 164.
According to the guidelines given in Table 164, the initial dose for this patient should be 250 to 750 mg every 12 hours. Because the patient’s
renal function is in the upper area of the CrClest adjustment range, the dose of 500 mg every 12 hours was prescribed.
Example 6
16:
1. Levetiracetam,
Estimate creatinine clearance.
Page 14 / 34
SAUDI
dosing (5 halflives = 5 • 11.7 h = 59 h or 2.5 d). Levetiracetam serum concentrations should also be measured if the patient DIGITALanLIBRARY
experiences
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Example 6
For adults, the initial dose of levetiracetam is 1000 mg/d, administered intravenously as divided doses every 12 hours. The drug is infused over
15 minutes. The dose is titrated up 1000 mg/d every 2 weeks as needed, and the patient is monitored for seizure frequency and adverse drug
effects. The maximum dose is usually 30004000 mg/d.
USE OF LEVETIRACETAM SERUM CONCENTRATIONS TO ALTER DOSES
A definitive therapeutic range for steadystate levetiracetam serum concentrations has not been established.9,10, and 11 Because of this, serum
concentration monitoring for levetiracetam plays only a supportive role in the dosing of the drug. Important patient parameters (seizure frequency,
potential levetiracetam side effects, etc) should be followed to confirm that the patient is responding to treatment and not developing adverse drug
reactions.6 However, there are clinical situations where levetiracetam serum concentrations can be very helpful.
Once dosage titration has been conducted, and an effective dose of levetiracetam has been established by assessing therapeutic response and
absence of adverse effects, many clinicians obtain a steadystate trough levetiracetam concentration to establish an individualized effective target
value for the patient. When this is done, if seizure frequency changes or an adverse effect occurs, another steadystate trough levetiracetam serum
concentration can be measured to ascertain potential solutions to the problem. For instance, if a patient suddenly has more seizures than usual,
comparing the current levetiracetam serum concentration with the established effective target levetiracetam concentration can be helpful to decide a
course of action. If the current levetiracetam concentration is lower than usual, reasons for the change can be explored (lack of adherence to therapy,
drug interaction, etc), and, if appropriate, a levetiracetam dosage increase can be considered to reestablish effective concentrations. If the current
levetiracetam concentration is about the same, changes to therapy may be warranted (increase levetiracetam dose, addition of other drug therapy,
etc). Alternatively, if a patient suddenly develops adverse effects that could be due to levetiracetam therapy, and the current levetiracetam serum
concentration is high, it may be appropriate to decrease the levetiracetam dose. Also, when an effective levetiracetam concentration has been
established for a patient, the effects of new drug therapy that may cause drug interactions or of new disease states or conditions that can alter
levetiracetam pharmacokinetics can be assessed prospectively by measuring current levetiracetam concentration before any clinical events occur.
When a levetiracetam dosage change is made, sufficient time to attain steadystate conditions (∼35 halflives) should be allowed before assessing
therapeutic outcome (see Table 162). Of course, any time adverse effects occur during dosage titration, measures should be taken to assess the
likelihood that they are due to levetiracetam treatment and appropriate action should be taken when needed.
If levetiracetam serum concentrations are measured in patients and a dosage change is necessary, clinicians should seek to use the simplest, most
straightforward method available to determine the steadystate concentration for the new regimen. In most cases, a simple dosage ratio can be used to
change doses since levetiracetam follows linear pharmacokinetics. In some situations, it may be necessary or desirable to compute levetiracetam
pharmacokinetic parameters for the patient and utilize these to calculate the steadystate concentration for a new dose. With two steadystate
Downloaded
concentrations 202443
obtained9:49 P Your
before IP is intravenous
and after 154.59.124.91
dose administration, it is possible to compute the levetiracetam pharmacokinetic parameters
for a patient using the OneCompartment Model Parameter method and utilize these to calculate the best drug dose. Finally, computerized methods
that incorporate expected population pharmacokinetic characteristics (Bayesian pharmacokinetic computer programs) can be used in difficult cases
where renal function is changing, serum concentrations are obtained at suboptimal times, or the patient was not at steadystate when serum
likelihood that they are due to levetiracetam treatment and appropriate action should be taken when needed.
If levetiracetam serum concentrations are measured in patients and a dosage change is necessary, clinicians should seek to use the
Access simplest,
Provided by: most
straightforward method available to determine the steadystate concentration for the new regimen. In most cases, a simple dosage ratio can be used to
change doses since levetiracetam follows linear pharmacokinetics. In some situations, it may be necessary or desirable to compute levetiracetam
pharmacokinetic parameters for the patient and utilize these to calculate the steadystate concentration for a new dose. With two steadystate
concentrations obtained before and after intravenous dose administration, it is possible to compute the levetiracetam pharmacokinetic parameters
for a patient using the OneCompartment Model Parameter method and utilize these to calculate the best drug dose. Finally, computerized methods
that incorporate expected population pharmacokinetic characteristics (Bayesian pharmacokinetic computer programs) can be used in difficult cases
where renal function is changing, serum concentrations are obtained at suboptimal times, or the patient was not at steadystate when serum
concentrations were measured. An additional benefit of this method is that a complete pharmacokinetic workup (determination of clearance, volume
of distribution, and halflife) can be done with one or more measured concentrations that do not have to be at steadystate.
When oral therapy is required, levetiracetam is usually given once daily for extendedrelease tablets or twice daily for the other oral dosage forms.
concentrationtime profile, a very simple pharmacokinetic equation that computes the average levetiracetam steadystate serum concentration (Css in
μg/mL = mg/L) is widely used and allows maintenance dosage calculation: Css = (D/τ)/(Cl/F) or D = Css(Cl/F)τ, where D is the dose of levetiracetam in
mg, Cl/F is levetiracetam hybrid clearance/bioavailability parameter in L/h, and τ is the dosage interval in hours.
If intravenous dosing is needed, levetiracetam is usually given twice daily as a 15minute infusion. For this route of administration, a predose steady
state trough concentration (Cssmin) is usually maintained in the desired concentration range: Cssmin = (De−kτ)/[V(1 − e−kτ)] or D = [Cssmin V(1 − e−kτ)]/(e
−kτ), where D is the dose of levetiracetam in mg, V is the volume of distribution in L, k is the elimination rate constant in h−1 [k = (0.693)/(t
1/2)], and τ is
the dosage interval in hours.
Linear Pharmacokinetics Method
Because levetiracetam follows linear, doseproportional pharmacokinetics, steadystate serum concentrations change in proportion to dose
according to the following equation: Dnew/Css,new = Dold/Css,old or Dnew = (Css,new/Css,old) Dold, where D is the dose, Css is the steadystate concentration,
old indicates the dose that produced the steadystate concentration that the patient is currently receiving, and new denotes the steadystate
concentration produced by the newly prescribed dose. The advantages of this method are that it is quick and simple. The disadvantage is steadystate
concentrations are required. Additionally, this method can be used with any route of administration to adjust doses of levetiracetam if only a single
steadystate concentration is available.
Example 7
KL is a 51yearold, 75kg (height = 5 ft 10 in) male with complex partial seizures who receives monotherapy with levetiracetam. He has normal liver
and renal function. KL was titrated to a dose of levetiracetam 1500 mg daily of extendedrelease tablets without any side effects and a decreased
seizure frequency. At that time, a steadystate levetiracetam trough concentration was obtained before a dose and equaled 30.2 μg/mL. Several
months ago, the patient was started on carbamazepine, and he has been on a stable dose for 4 weeks. Today, the steadystate levetiracetam trough
concentration obtained before the next dose was 24.5 μg/mL. Suggest a new maintenance dosage regimen using extendedrelease levetiracetam
tablets to reestablish the original levetiracetam steadystate concentration for this patient.
1. Compute new dose to achieve the desired serum concentration.
Using linear pharmacokinetics, the new levetiracetam dose would equal: Dnew = (Cssnew/Cssold) Dold = (30.2 μg/mL/24.5 μg/mL) 1500 mg/d = 1849
mg/d, rounded to 1750 mg/d.
The patient should be carefully monitored for seizure frequency and adverse effects. If desired, steadystate levetiracetam trough serum
concentrations can be measured 35 halflives after the dosage change has been made (see Table 162: ∼t1/2 = 6.1 hours, ∼35 t1/2 in 12 days).
Pharmacokinetic Parameter Method
The Pharmacokinetic Parameter method of adjusting drug doses was among the first techniques available to change doses using serum
concentrations. It allows the computation of an individual’s own, unique pharmacokinetic constants and uses those to calculate the steadystate
concentration
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Reserved. levetiracetam dosage regimen.
of Use • Privacy For patients
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method requires that steadystate has been achieved and uses only a single steadystate levetiracetam concentration (Css). Levetiracetam Cl/F can be
calculated using the following formula: Cl/F = (D/τ)/Css, where D is the dose of levetiracetam in mg, Cl/F is levetiracetam hybrid
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The Pharmacokinetic Parameter method of adjusting drug doses was among the first techniques available to change doses using serum
concentrations. It allows the computation of an individual’s own, unique pharmacokinetic constants and uses those to calculate the steadystate
concentration that is achieved from a desired levetiracetam dosage regimen. For patients receiving oral levetiracetam, the Pharmacokinetic Parameter
method requires that steadystate has been achieved and uses only a single steadystate levetiracetam concentration (Css). Levetiracetam Cl/F can be
calculated using the following formula: Cl/F = (D/τ)/Css, where D is the dose of levetiracetam in mg, Cl/F is levetiracetam hybrid
clearance/bioavailability parameter in L/h, and τ is the dosage interval in hours. The corresponding equation used for intravenously administered
drug is: Cl = (D/τ)/Css.
To illustrate the similarities and differences between this method of dosage calculation and the Pharmacokinetic Parameter method, the same
example used in the previous section will be used.
Example 8
KL is a 51yearold, 75kg (height = 5 ft 10 in) male with complex partial seizures who receives monotherapy with levetiracetam. He has normal liver
and renal function. KL was titrated to a dose of levetiracetam 1500 mg daily of extendedrelease tablets without any side effects and a decreased
seizure frequency. At that time, a steadystate levetiracetam trough concentration was obtained before a dose and equaled 30.2 μg/mL. Several
months ago, the patient was started on carbamazepine, and he has been on a stable dose for 4 weeks. Today, the steadystate levetiracetam trough
concentration obtained before the next dose was 24.5 μg/mL. Suggest a new maintenance dosage regimen using extendedrelease levetiracetam
tablets to reestablish the original levetiracetam steadystate concentration for this patient.
1. Compute pharmacokinetic parameters.
Levetiracetam Cl/F can be computed using a steadystate levetiracetam trough concentration: Cl/F = (D/τ)/Css = [(1500 mg)/(24 h)]/(24.5 mg/L) =
2.55 L/h. (Note: μg/mL = mg/L and this concentration unit was substituted for Css in the calculations so that unnecessary unit conversion was not
required.)
2. Compute the new levetiracetam dosage.
Levetiracetam Cl/F is used to compute the new dose: D = Css(Cl/F)τ = 30.2 mg/L(2.55 L/h) 24 h = 1848 mg, rounded to 1750 mg every 24 hours.
OneCompartment Model Parameter Method
The OneCompartment Model Parameter method of adjusting drug doses was among the first techniques available to change doses using serum
concentrations.43 It allows the computation of an individual’s own, unique pharmacokinetic constants and uses those to calculate a dose that achieves
the desired levetiracetam concentrations. The standard OneCompartment Model Parameter method conducts a small pharmacokinetic experiment
using three to four levetiracetam serum concentrations obtained during a dosage interval and does not require steadystate conditions. The Steady
State OneCompartment Model Parameter method assumes that steadystate has been achieved and requires only a steadystate peak and trough
concentration pair obtained before and after a dose. Onecompartment model intravenous bolus equations are used successfully to dose drugs that
are given by infusion when the infusion time is less than the drug halflife.44
Standard OneCompartment Model Parameter Method
The standard version of the OneCompartment Model Parameter method does not require steadystate concentrations. A trough levetiracetam
concentration is obtained before a dose, a peak levetiracetam concentration is obtained after the dose is infused (½ hour after a 15 minute infusion),
and one to two additional postdose serum levetiracetam concentrations are obtained (Figure 161). Ideally, the one to two postdose concentrations
should be obtained at least 1 estimated halflife from each other to minimize the influence of assay error. The postdose serum concentrations are used
to calculate the levetiracetam elimination rate constant and halflife (see Figure 161). The halflife can be computed by graphing the postdose
concentrations on semilogarithmic paper, drawing the best straight line through the data points, and determining the time needed for serum
concentrations to decline by onehalf. Once the halflife is known, the elimination rate constant (k) can be computed: k = 0.693/(t1/2). Alternatively, the
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concentrations [k = (ln C1 − ln C2)/Δt], where C1 and C2 are postdose
serum concentrations and Δt is the time that expired between the times that C1 and C2 were obtained, and the halflife can be computed using the
The standard version of the OneCompartment Model Parameter method does not require steadystate concentrations. A trough levetiracetam
SAUDI
concentration is obtained before a dose, a peak levetiracetam concentration is obtained after the dose is infused (½ hour after DIGITAL
a 15 minute LIBRARY
infusion),
and one to two additional postdose serum levetiracetam concentrations are obtained (Figure 161). Ideally, the one to two postdose concentrations
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should be obtained at least 1 estimated halflife from each other to minimize the influence of assay error. The postdose serum concentrations are used
to calculate the levetiracetam elimination rate constant and halflife (see Figure 161). The halflife can be computed by graphing the postdose
concentrations on semilogarithmic paper, drawing the best straight line through the data points, and determining the time needed for serum
concentrations to decline by onehalf. Once the halflife is known, the elimination rate constant (k) can be computed: k = 0.693/(t1/2). Alternatively, the
elimination rate constant can be directly calculated using the postdose serum concentrations [k = (ln C1 − ln C2)/Δt], where C1 and C2 are postdose
serum concentrations and Δt is the time that expired between the times that C1 and C2 were obtained, and the halflife can be computed using the
elimination rate constant (t1/2 = 0.693/k). The volume of distribution (V) is calculated using the following equation: V = D/(Cmax − Cmin) where D is the
levetiracetam dose, Cmax is the peak concentration and Cmin is the trough concentration. The elimination rate constant and volume of distribution
measured in this fashion are the patient’s own, unique levetiracetam pharmacokinetic constants and can be used in onecompartment model
intravenous bolus equations to compute the required dose to achieve any desired serum concentration.
FIGURE 161
The One Compartment Model Parameter method for individualization of levetiracetam doses uses a trough (Cmin), peak (Cmax), and one to two
additional postdose concentrations (C3, C4) to compute a patient’s own, unique pharmacokinetic parameters. This version of the One Compartment
Model Parameter method does not require steadystate conditions. The peak and trough concentrations are used to calculate the volume of
distribution, and the postdose concentrations (Cmax, C3, C4) are used to compute halflife. Once the volume of distribution and halflife have been
measured, they can be used to compute the exact dose needed to achieve desired levetiracetam concentrations.
SteadyState OneCompartment Model Parameter Method
If a steadystate peak and trough levetiracetam concentration pair is available for a patient, the OneCompartment Model Parameter method can be
used to compute patient pharmacokinetic parameters and levetiracetam doses (Figure 162). Since the patient is at steadystate, the measured trough
concentration obtained before the dose was given can be extrapolated to the next dosage time and used to compute the levetiracetam elimination rate
constant [k = (ln Cssmax − ln Cssmin)/(τ − t′), where Cssmax and Cssmin are the steadystate peak and trough serum concentrations and t′ and τ are the
combined infusion time plus waiting time and dosage interval, respectively], and the halflife can be computed using the elimination rate constant (t1/2
= 0.693/k). The volume of distribution (V) is calculated using the following equation: V = D/(Cssmax − Cssmin) where D is the levetiracetam dose, Cssmax
is the steadystate peak concentration, and Cssmin is the steadystate trough concentration. The elimination rate constant and volume of distribution
measured in this way are the patient’s own, unique levetiracetam pharmacokinetic constants and can be used in onecompartment model intravenous
bolus equations to compute the required dose to achieve any desired serum concentration. The dosage calculations are similar to those done in the
initial dosage section of this chapter, except that the patient’s real pharmacokinetic parameters are used in the equations instead of population
pharmacokinetic estimates.
FIGURE 162
The steadystate version of the One Compartment Model Parameter method uses a steadystate peak (Cssmax) and trough (Cssmin) concentration pair
to individualize levetiracetam therapy. Because the patient is at steadystate, consecutive trough concentrations will be identical, so the trough
concentration can be extrapolated to the next predose time. The steadystate peak and trough concentrations are used to calculate the volume of
Downloaded 202443
distribution and 9:49
halflife. P the
Once Your IP is 154.59.124.91
volume of distribution and halflife have been measured, they can be used to compute the exact dose needed to
achieve the desired levetiracetam concentrations.
FIGURE 162 SAUDI DIGITAL LIBRARY
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The steadystate version of the One Compartment Model Parameter method uses a steadystate peak (Cssmax) and trough (Cssmin) concentration pair
to individualize levetiracetam therapy. Because the patient is at steadystate, consecutive trough concentrations will be identical, so the trough
concentration can be extrapolated to the next predose time. The steadystate peak and trough concentrations are used to calculate the volume of
distribution and halflife. Once the volume of distribution and halflife have been measured, they can be used to compute the exact dose needed to
achieve the desired levetiracetam concentrations.
Example 9
increases have been tried with carbamazepine, but they have been unsuccessful due to development of adverse effects. The patient was started on
an initial levetiracetam dosage regimen using intravenous drug of 1000 mg every 12 hours designed to achieve a steadystate trough levetiracetam
concentration equal to 15 μg/mL 4 days ago, but seizure frequency did not markedly change. To assist in dosage adjustment, steadystate
levetiracetam concentrations were drawn just before a dose (Cssmin = 7.9 μg/mL) and 30 minutes after a 15minute infusion (Cssmax = 29.6 μg/mL).
Compute a new intravenous levetiracetam dosage regimen designed to achieve a steadystate trough concentration equal to 12 μg/mL.
This patient has a CrClest >80 mL/min, so levetiracetam t1/2 is expected to be 6.1 h (see Table 162). After 4 days of treatment with levetiracetam,
the patient is at steadystate.
2. Use SteadyState OneCompartment Model Parameter method to compute a new dose.
a. Compute the patient’s elimination rate constant and halflife (note: t′ = infusion time + waiting time of 15 minutes and ½ hour, respectively).
b. Compute the patient’s volume of distribution.
c. Choose a new steadystate trough concentration.
For the purposes of this example, the desired steadystate trough concentration will be 12 μg/mL.
d. Determine the new dosage interval for the desired concentrations.
For levetiracetam, a dosage interval of 12 hours is used for most patients (see Table 164).
e. Determine the new dose for the desired concentrations.
The dose is computed using the onecompartment model intravenous bolus equation utilized in the initial dosing section of this chapter:
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be prescribed.
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Example 9
increases have been tried with carbamazepine, but they have been unsuccessful due to development of adverse effects. The patient was started on
an initial levetiracetam dosage regimen using intravenous drug of 1000 mg every 12 hours designed to achieve a steadystate trough levetiracetam
concentration equal to 15 μg/mL 4 days ago, but seizure frequency did not markedly change. To assist in dosage adjustment, steadystate
levetiracetam concentrations were drawn just before a dose (Cssmin = 7.9 μg/mL) and 30 minutes after a 15minute infusion (Cssmax = 29.6 μg/mL).
Compute a new intravenous levetiracetam dosage regimen designed to achieve a steadystate trough concentration equal to 12 μg/mL.
2. Use SteadyState OneCompartment Model Parameter method to compute a new dose.
a. Compute the patient’s elimination rate constant and halflife (note: t′ = infusion time + waiting time of 15 minutes and ½ hour, respectively).
b. Compute the patient’s volume of distribution.
c. Choose a new steadystate trough concentration.
For the purposes of this example, the desired steadystate trough concentration will be 12 μg/mL.
d. Determine the new dosage interval for the desired concentrations.
e. Determine the new dose for the desired concentrations.
The dose is computed using the onecompartment model intravenous bolus equation utilized in the initial dosing section of this chapter:
A dose of levetiracetam 1750 mg every 12 hours would be prescribed.
BAYESIAN PHARMACOKINETIC COMPUTER PROGRAMS

Computer programs are available that can assist in the computation of pharmacokinetic parameters for patients. The most reliable computer
programs use a nonlinear regression algorithm that incorporates components of Bayes theorem.45 Nonlinear regression is a statistical technique that
uses an iterative process to compute the best pharmacokinetic parameters for a concentrationtime data set. Briefly, the patient’s drug dosage
schedule and serum concentrations are input into the computer. The computer program has a pharmacokinetic equation preprogrammed for the
drug and administration method (oral, intravenous bolus, intravenous infusion, etc). Typically, a onecompartment model is used, although some
programs allow the user to choose among several different equations. Using population estimates based on demographic information for the patient
(age, weight, gender, liver function, cardiac status, etc) supplied by the user, the computer program then computes estimated serum concentrations at
each time there are actual serum concentrations. The computer program then changes kinetic parameters, and a new set of estimated serum
concentrations are computed. The pharmacokinetic parameters that generated the estimated serum concentrations closest to the actual values are
remembered by the computer program, and the process is repeated until the set of pharmacokinetic parameters that result in estimated serum
concentrations
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compute improved dosing schedules for patients. Bayes theorem is used in the computer algorithm to balance the results of the computations
between values based solely on the patient’s serum drug concentrations and those based only on patient population parameters. Results from studies
schedule and serum concentrations are input into the computer. The computer program has a pharmacokinetic equation preprogrammed for the
drug and administration method (oral, intravenous bolus, intravenous infusion, etc). Typically, a onecompartment model isSAUDI DIGITALsome
used, although LIBRARY
programs allow the user to choose among several different equations. Using population estimates based on demographic information
Access Providedfor
by: the patient
(age, weight, gender, liver function, cardiac status, etc) supplied by the user, the computer program then computes estimated serum concentrations at
each time there are actual serum concentrations. The computer program then changes kinetic parameters, and a new set of estimated serum
concentrations are computed. The pharmacokinetic parameters that generated the estimated serum concentrations closest to the actual values are
remembered by the computer program, and the process is repeated until the set of pharmacokinetic parameters that result in estimated serum
concentrations that are statistically closest to the actual serum concentrations are generated. These pharmacokinetic parameters can then be used to
compute improved dosing schedules for patients. Bayes theorem is used in the computer algorithm to balance the results of the computations
between values based solely on the patient’s serum drug concentrations and those based only on patient population parameters. Results from studies
that compare various methods of dosage adjustment have consistently found that these types of computerdosing programs perform at least as well
as experienced clinical pharmacokineticists and clinicians and better than inexperienced clinicians.
Some clinicians use Bayesian pharmacokinetic computer programs exclusively to alter drug doses based on serum concentrations. An advantage of
this approach is that consistent dosage recommendations are made when several different practitioners are involved in therapeutic drug monitoring
programs. However, since simpler dosing methods work just as well for patients with stable pharmacokinetic parameters and steadystate drug
concentrations, many clinicians reserve the use of computer programs for more difficult situations. Those situations include serum concentrations
that are not at steadystate, serum concentrations not obtained at the specific times needed to employ simpler methods, and unstable
pharmacokinetic parameters. Many Bayesian pharmacokinetic computer programs are available to users, and most should provide answers similar to
the one used in the following examples. The program used to solve problems in this book is DrugCalc written by Dr Dennis Mungall.45
Example 10
LK is a 13yearold, 47kg (height = 5 ft 1 in) female with partial seizures who requires therapy with oral levetiracetam. The patient has normal liver
and renal function (bilirubin = 0.5 mg/dL, albumin 4.6 mg/dL, serum creatinine = 0.5 mg/dL), and she is taking carbamazepine. After dosage
titration, the patient was prescribed 750 mg every 12 hours of levetiracetam immediaterelease tablets for 2 weeks, and the steadystate
levetiracetam trough concentration equals 9.1 μg/mL. The patient is assessed to be adherent with her dosage regimen. Suggest a levetiracetam
dosage regimen designed to achieve a steadystate levetiracetam trough concentration of 15 μg/mL.
1. Enter the patient’s demographic, drugdosing, and serum concentration/time data into the computer program.
2. Compute pharmacokinetic parameters for the patient using Bayesian pharmacokinetic computer program.
The pharmacokinetic parameters computed by the program are a volume of distribution of 33 L, a halflife equal to 4.7 h, and a clearance equal
to 58 mL/min.
3. Compute dose required to achieve the desired levetiracetam serum concentrations.
The onecompartment model firstorder absorption equations used by the program to compute doses indicates that a dose of 1250 mg every 12
hours will produce a steadystate levetiracetam trough concentration of 15.8 μg/mL.
DOSING STRATEGIES
Initial dose and dosage adjustment techniques using serum concentrations can be used in any combination as long as the limitations of each method
are observed. Some dosing schemes link together logically when considered according to their basic approaches or philosophies. Dosage strategies
that follow similar pathways are given in Table 166.
TABLE 166
Dosing Strategies
Dosing
Initial Dosing Use of Serum Concentrations to Alter Doses
Approach/Philosophy
Pharmacokinetic Pharmacokinetic Dosing method Pharmacokinetic Parameter method (any route) or One Compartment Model
parameter/equations Parameter method (intravenous)

Literaturebased/concept
16: Levetiracetam, Literaturebased Recommended Linear Pharmacokinetics method Page 21 / 34
Dosing method
Computerized Bayesian computer program Bayesian computer program

DOSING STRATEGIES
Initial dose and dosage adjustment techniques using serum concentrations can be used in any combination as long as the limitations of each method
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are observed. Some dosing schemes link together logically when considered according to their basic approaches or philosophies. Dosage strategies
that follow similar pathways are given in Table 166.
TABLE 166
Dosing Strategies
Dosing
Initial Dosing Use of Serum Concentrations to Alter Doses
Approach/Philosophy
Pharmacokinetic Pharmacokinetic Dosing method Pharmacokinetic Parameter method (any route) or One Compartment Model
parameter/equations Parameter method (intravenous)
Literaturebased/concept Literaturebased Recommended Linear Pharmacokinetics method

Dosing method
Computerized Bayesian computer program Bayesian computer program
SPECIAL DOSING CONSIDERATIONS

Conversion of Patient Doses Between Dosage Forms
The bioavailability of levetiracetam for oral solution, immediaterelease tablets, and sustainedrelease tablets are all similar (F = 0.92). Because of this,
patients can be switched between oral dosage forms using the same dose for each. However, since the absorption characteristics are different (Tmax =
0.8 hour for oral solution, Tmax = 1.5 hours for immediate release tablets, and Tmax = 4.5 hours for extendedrelease tablets), there will be some small
differences in steadystate trough levetiracetam concentrations. Because there is such a small difference between oral bioavailability and the
bioavailability for the intravenous drug (F = 1), patients can be switched between any of the oral dosage forms and the intravenous form without
dosage alteration. Should a patient experience increased seizure frequency or adverse effects attributable to levetiracetam after a dosage form
change, a steadystate levetiracetam concentration can be measured to see if it has been altered by the conversion.
PROBLEMS
The following problems are intended to emphasize the computation of initial and individualized doses using clinical pharmacokinetic techniques.
Clinicians should always consult the patient’s chart to confirm that current anticonvulsant therapy is appropriate. Additionally, all other medications
that the patient is taking, including prescription and nonprescription drugs, should be noted and checked to ascertain if a potential drug interaction
with levetiracetam exists.
1. FH is a 37yearold, 85kg (height = 6 ft 1 in) male with tonicclonic seizures who requires therapy with oral levetiracetam monotherapy. He has
normal liver and renal function (Scr = 1.1 mg/dL). Suggest an initial levetiracetam dosage regimen using extendedrelease tablets designed to
achieve a steadystate levetiracetam concentration equal to 15 μg/mL.
2. Patient FH (see problem 1) was prescribed 1000 mg every 24 hours of levetiracetam extendedrelease tablets for 2 weeks, and the steadystate
levetiracetam trough concentration equals 12.9 μg/mL. The patient is assessed to be adherent with his dosage regimen. Suggest a levetiracetam
3. AS is a 9yearold, 35kg female (height = 54 in) with complex partial seizures who requires therapy with oral levetiracetam immediaterelease
tablets. She has normal liver and renal function (Scr = 0.6 mg/dL). AS also takes carbamazepine to treat her epilepsy. Suggest an initial
levetiracetam dosage regimen designed to achieve a steadystate levetiracetam concentration equal to 20 μg/mL.
4. Patient AS (see problem 3) was prescribed 500 mg every 12 hours of levetiracetam immediaterelease tablets for 3 weeks, and the steadystate
dosage regimen designed to achieve a steadystate levetiracetam trough concentration equal to 15 μg/mL.
5. FL is a 29yearold, 75kg (height = 5 ft 11 in) male with simple partial seizures who requires therapy with oral levetiracetam immediaterelease
tablets.
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• Privacy (Scr = •3.6 mg/dL),
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4. Patient AS (see problem 3) was prescribed 500 mg every 12 hours of levetiracetam immediaterelease tablets for 3 weeks, Access
and theProvided by:
steadystate
dosage regimen designed to achieve a steadystate levetiracetam trough concentration equal to 15 μg/mL.
5. FL is a 29yearold, 75kg (height = 5 ft 11 in) male with simple partial seizures who requires therapy with oral levetiracetam immediaterelease
tablets. He has normal liver function, has impaired renal function (Scr = 3.6 mg/dL), and is also receiving phenytoin therapy. Suggest an initial
6. Patient FL (see problem 5) was prescribed 500 mg every 12 hours of levetiracetam immediaterelease tablets for 4 weeks, and the steadystate
levetiracetam trough concentration equaled 15.7 μg/mL. The patient is assessed to be adherent with his dosage regimen. Suggest a levetiracetam
7. PH is a 4yearold, 22kg male (height = 40 in) with tonicclonic seizures who requires therapy with levetiracetam oral solution. He has normal liver
and renal function (Scr = 0.5 mg/dL) and is also treated with valproate sodium. Suggest an initial levetiracetam dosage regimen designed to achieve
a steadystate levetiracetam concentration equal to 15 μg/mL.
8. Patient PH (see problem 7) was prescribed 300 mg every 12 hours of levetiracetam oral solution for 2 weeks, and the steadystate levetiracetam
trough concentration equals 25.5 μg/mL. The patient is assessed to be adherent with his dosage regimen. Suggest a levetiracetam dosage regimen
designed to achieve a steadystate levetiracetam trough concentration of 17 μg/mL.
9. HF is a 37yearold, 85kg (height = 6 ft 1 in) male with tonicclonic seizures who requires therapy with oral levetiracetam monotherapy. He has
severe liver disease (ChildPugh score of 12) and a Scr = 1.5 mg/dL. Suggest an initial levetiracetam dosage regimen using extendedrelease tablets
designed to achieve a steadystate levetiracetam concentration equal to 15 μg/mL.
10. LK is a 50yearold, 70kg (height = 5 ft 10 in) male with complex partial seizures who requires therapy with levetiracetam. His serum creatinine
equals 0.9 mg/dL. He has normal liver function and is currently taking phenytoin sodium capsules (steadystate concentration = 17.8 μg/mL).
Additional dosage increases have been tried with phenytoin, but they have been unsuccessful due to development of adverse effects. The patient
was started on an initial levetiracetam dosage regimen using intravenous drug of 1000 mg every 12 hours designed to achieve a steadystate trough
levetiracetam concentration equal to 15 μg/mL 4 days ago, but seizure frequency did not markedly change. To assist in dosage adjustment, steady
state levetiracetam concentrations were drawn just before a dose (Cssmin = 7.9 μg/mL) and 30 minutes after a 15 minute infusion (Cssmax = 29.6
μg/mL). Compute a new intravenous levetiracetam dosage regimen designed to achieve a steadystate trough concentration equal to 15 μg/mL.
11. UP is a 55yearold, 68kg (height = 5 ft 8 in) male with complex partial seizures who was given a new prescription for 1000 mg daily of levetiracetam
extendedrelease tablets. He has normal liver and renal (bilirubin = 0.7 mg/dL, albumin = 4.0 g/dL, serum creatinine = 1.1 mg/dL) function, and also
takes 400 mg/d of phenytoin. The levetiracetam concentration at 6 hours after the third dose equals 8 μg/mL. Compute a levetiracetam dose that
will provide a steadystate trough concentration of 20 μg/mL.
ANSWERS TO PROBLEMS
1. Answer to problem 1.
The Cl/F rate for a patient taking levetiracetam monotherapy is 0.90 mL/min/kg: Cl/F = (0.90 mL/min/kg)85 kg = 76.5 mL/min. The estimated V/F
would be 0.56 L/kg, and the estimated halflife equals 7.3 h.
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Levetiracetam 9:49 P Your IP tablets
extendedrelease is 154.59.124.91
will be prescribed to this patient. (Note: μg/mL = mg/L and this concentration unit was substituted for
mg/L • 76.5 mL/min • 24 h • 60 min/h)/(1000 mL/L) = 1652 mg, rounded to 1500 mg every 24 hours (dose rounded down to accommodate
extendedrelease dosage form).
The Cl/F rate for a patient taking levetiracetam monotherapy is 0.90 mL/min/kg: Cl/F = (0.90 mL/min/kg)85 kg = 76.5 mL/min. The estimated V/F
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would be 0.56 L/kg, and the estimated halflife equals 7.3 h.
Levetiracetam extendedrelease tablets will be prescribed to this patient. (Note: μg/mL = mg/L and this concentration unit was substituted for
mg/L • 76.5 mL/min • 24 h • 60 min/h)/(1000 mL/L) = 1652 mg, rounded to 1500 mg every 24 hours (dose rounded down to accommodate
extendedrelease dosage form).
dosing (5 halflives = 5 • 7.3 h = 36.5 h or 1.5 d). Levetiracetam serum concentrations should also be measured if the patient experiences an
For adults, the initial dose of levetiracetam is 1000 mg/d, administered every 24 hours for extendedrelease tablets. The dose is titrated up 1000
mg/d every 2 weeks as needed, and the patient is monitored for seizure frequency and adverse drug effects. The maximum dose is usually 3000
4000 mg/d.
dosing (5 halflives = 5 • 7.3 h = 36.5 h or 1.5 d). Levetiracetam serum concentrations should also be measured if the patient experiences an
Using linear pharmacokinetics, the new levetiracetam dose would equal: Dnew = (Cssnew/Cssold) Dold = (20.0 μg/mL/12.9 μg/mL) 1000 mg/d =
1550 mg/d, rounded to 1500 mg/d. The new dose is 1500 mg every 24 hours.
3.23 L/h. (Note: μg/mL = mg/L and this concentration unit was substituted for Css in the calculations so that unnecessary unit conversion was
not required.)
Levetiracetam Cl/F is used to compute the new dose: D = Css(Cl/F)τ = 20 mg/L(3.23 L/h) 24 h = 1550 mg, rounded to 1500 mg every 24 hours.
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35154.59.124.91
halflives after the dosage change has been made (see Table 162: ∼t1/2 = 7.3 hours, ∼35 t1/2 in 12 days).

not required.)
2. Compute the new levetiracetam dosage. Access Provided by:
This patient has a stable serum creatinine and is not obese. The equation for pediatric patients age 120 years is: CrClest (in mL/min/1.73 m2) =
(0.55 • Ht)/SCr, where Ht is in cm and SCr is in mg/dL (Chapter 3):
This patient has a CrClest >80 mL/min/1.73 m2, so levetiracetam clearance will not need to be adjusted for renal function (see Table 162).
The Cl/F rate for a pediatric patient taking levetiracetam concurrently with carbamazepine is 1.23 mL/min/kg: Cl/F = (1.23 mL/min/kg)35 kg =
43.1 mL/min. The estimated halflife equals 4.4 h.
Css in the calculations so that unnecessary unit conversion was not required). The dosage equation for oral levetiracetam is: D = Css(Cl/F)τ = (20
expected to have a halflife equal to 4.4 hours, the levetiracetam steadystate concentration could be obtained any time after the first day of
dosing (5 halflives = 5 • 4.4 h = 22 h or ∼1 d). Levetiracetam serum concentrations should also be measured if the patient experiences an
This patient has a stable serum creatinine and is not obese. The equation for pediatric patients age 120 years is: CrClest (in mL/min/1.73 m2) =
For children, the initial dose of levetiracetam is 20 mg/kg/d, administered as divided doses every 12 hours for immediaterelease tablets (20
mg/kg/d • 35 kg = 700 mg/d, rounded to 250 mg every 12 hours). The dose is titrated up 20 mg/kg/d every 2 weeks as needed, and the patient is
monitored for seizure frequency and adverse drug effects. The maximum dose is usually 60 mg/kg/d.
exacerbation
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9:49 epilepsy
P Your IP or ifisthe patient develops potential signs or symptoms of levetiracetam toxicity.
154.59.124.91
4. Answer
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monitored for seizure frequency and adverse drug effects. The maximum dose is usually 60 mg/kg/d.
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1. Compute new dose to achieve desired serum concentration.
Using linear pharmacokinetics, the new levetiracetam dose would equal: Dnew = (Cssnew/Cssold) Dold = (15.0 μg/mL/8.3 μg/mL) 1000 mg/d = 1807
mg/d, rounded to 2000 mg/d. The new dose is 1000 mg every 12 hours.
concentrations can be measured 35 halflives after the dosage change has been made (see Table 162: ∼t1/2 = 4.4 hours, ∼35 t1/2 in ∼1 day).
not required.)
Compute the new levetiracetam dosage.
Levetiracetam Cl/F is used to compute the new dose: D = Css(Cl/F)τ = 15 mg/L(5.02 L/h)12 h = 904 mg, rounded to 1000 mg every 12 hours.
concentrations can be measured 35 halflives after the dosage change has been made (see Table 162: ∼t1/2 = 4.4 hours, ∼35 t1/2 in ∼1 day).
This patient has a CrClest <80 mL/min, so levetiracetam clearance will need to be adjusted for renal function (see Table 162). The clearance for
this patient will be 50% of the normal value.
The Cl/F rate for a patient taking levetiracetam with phenytoin is 1.17 mL/min/kg, and the Cl/F is adjusted for reduced renal function: Cl/F =
0.5(1.17 mL/min/kg)75 kg = 43.9 mL/min. The estimated V/F would be 0.6 L/kg, and the estimated halflife equals 11.8 h: t1/2 = [0.693(V/F)]/(Cl/F)
= [0.693(0.6 L/kg)(1000 mL/L)]/[0.5(1.17 mL/min/kg)(60 min/h)] = 11.8 h.
1. Estimate creatinine clearance

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1. Estimate creatinine clearance
This patient has a CrClest <80 mL/min, so levetiracetam clearance will need to be adjusted for renal function (see Table 164).
To normalize CrClest (in mL/min) to a standard body surface area of 1.73 m2 (mL/min/1.73 m2), first compute the patient’s own body surface
area (BSA in m2): BSA = 0.007184 • W0.425 • H0.725 = 0.007184 • (75 kg)0.425 • [(71 in)(2.54 cm/in)]0.725 = 1.95 m2, CrClest (in mL/min/1.73 m2) =
[(CrClest)/(BSA)]1.73 m2 = [(32 mL/min)/(1.95 m2)]1.73 m2 = 28.4 mL/min/1.73 m2).
For adults with CrClest <30 mL/min/1.73 m2, the initial dose of levetiracetam is reduced (see Table 164). For this patient, the dose of 500 mg
every 12 hours for immediaterelease tablets was selected because his renal function was in the upper end of the range. The dose is titrated up
5001000 mg/d every 23 weeks as needed, and the patient is monitored for seizure frequency and adverse drug effects. The maximum dose is
usually 30004000 mg/d, but may need to be adjusted due to renal dysfunction.
expected to have a prolonged halflife, the levetiracetam steadystate concentration could be obtained any time after ∼57 days of dosing.
Levetiracetam serum concentrations should also be measured if the patient experiences an exacerbation of their epilepsy or if the patient
develops potential signs or symptoms of levetiracetam toxicity.
Using linear pharmacokinetics, the new levetiracetam dose would equal: Dnew = (Cssnew/Cssold) Dold = (24.0 μg/mL/15.7 μg/mL) 1000 mg/d =
1529 mg/d, rounded to 1500 mg/d. The new dose is 750 mg every 12 hours.
expected to have a prolonged halflife, the levetiracetam steadystate concentration could be obtained any time after ∼57 days of dosing.
Levetiracetam serum concentrations should also be measured if the patient experiences an exacerbation of their epilepsy or if the patient
develops potential signs or symptoms of levetiracetam toxicity.
not required.)
A steadystate
Downloaded 202443 trough
9:49 Plevetiracetam serum concentration can be measured after steadystate is attained in 35 halflives. Since the patient is
Your IP is 154.59.124.91
16: Levetiracetam, Pageday
expected to have a halflife equal to 11.8 hours, the levetiracetam steadystate concentration could be obtained any time after the third 27 /of34
not required.)
2. Compute the new levetiracetam dosage. Access Provided by:
This patient has a stable serum creatinine and is not obese. The equation for pediatric patients age 120 years: CrClest (in mL/min/1.73 m2) =
The Cl/F rate for a pediatric patient taking levetiracetam concurrently with valproate sodium is 1.08 mL/min/kg: Cl/F = (1.08 mL/min/kg)22 kg =
23.8 mL/min. The estimated halflife equals 5.2 h.
Levetiracetam oral solution will be prescribed to this patient. (Note: μg/mL = mg/L and this concentration unit was substituted for Css in the
calculations so that unnecessary unit conversion was not required.) The dosage equation for oral levetiracetam is: D = Css(Cl/F)τ = (15 mg/L •
23.8 mL/min • 12 h • 60 min/h)/(1000 mL/L) = 257 mg, rounded to 250 mg every 12 hours.
dosing (5 halflives = 5 • 5.2 h = 26 h or ∼1.1 d). Levetiracetam serum concentrations should also be measured if the patient experiences an
This patient has a stable serum creatinine and is not obese. The equation for pediatric patients age 120 years, CrClest (in mL/min/1.73 m2) =
This patient has a CrClest greater than 80 mL/min/1.73 m2, so levetiracetam clearance will not need to be adjusted for renal function (see Table
162).
For children, the initial dose of levetiracetam is 20 mg/kg/d, administered as divided doses every 12 hours for oral solution (20 mg/kg/d • 22 kg =
440 mg/d, rounded to 200 mg every 12 hours). The dose is titrated up 20 mg/kg/d every 2 weeks as needed, and the patient is monitored for
seizure frequency and adverse drug effects. The maximum dose is usually 60 mg/kg/d.
A steadystate
Downloaded 202443 trough levetiracetam
9:49 P serum concentration can be measured after steadystate is attained in 35 halflives. Since the patient is
Your IP is 154.59.124.91
16: Levetiracetam, Page 28
expected to have a halflife equal to 5.2 hours, the levetiracetam steadystate concentration could be obtained any time after the second day/ 34
of
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McGraw Hill. All Rights Reserved. Terms of Use • Privacy Policy • Notice • Accessibility
(5 halflives = 5 • 5.2 h = 26 h or ∼1.1 d). Levetiracetam serum concentrations should also be measured if the patient experiences an
For children, the initial dose of levetiracetam is 20 mg/kg/d, administered as divided doses every 12 hours for oral solution (20 mg/kg/d • 22 kg =
Access Provided by:
440 mg/d, rounded to 200 mg every 12 hours). The dose is titrated up 20 mg/kg/d every 2 weeks as needed, and the patient is monitored for
seizure frequency and adverse drug effects. The maximum dose is usually 60 mg/kg/d.
dosing (5 halflives = 5 • 5.2 h = 26 h or ∼1.1 d). Levetiracetam serum concentrations should also be measured if the patient experiences an
Using linear pharmacokinetics, the new levetiracetam dose would equal: Dnew = (Cssnew/Cssold) Dold = (17 μg/mL/25.5 μg/mL) 600 mg/d = 400
mg/d. The new dose is 200 mg every 12 hours.
concentrations can be measured 35 halflives after the dosage change has been made (see Table 162: ∼t1/2 = 5.2 hours, ∼35 t1/2 in ∼12 days).
not required.)
Levetiracetam Cl/F is used to compute the new dose: D = Css(Cl/F)τ = 17 mg/L(0.98 L/h)12 h = 200 mg, dose is 200 mg every 12 hours.
concentrations can be measured 3–5 halflives after the dosage change has been made (see Table 162: ∼t1/2 = 5.2 hours, ∼35 t1/2 in ∼12 days).
To compute the patient’s own body surface area (BSA in m2): BSA = 0.007184 • W0.425 • H0.725 = 0.007184 • (85 kg)0.425 • [(73 in)(2.54 cm/in)]0.725 =
2.09 m2.
The Cl/F rate for a patient taking levetiracetam monotherapy and severe liver disease is 29.2 mL/min/1.73 m2: Cl/F = [(29.2 mL/min)/(1.73 m2)]
2.09 m2 = 35.3 mL/min. The estimated V/F would be ∼45 L, and the estimated halflife equals 18.4 h.
Downloaded
mg/L • 202443
35.3 mL/min 9:49• 24
P hYour IP is 154.59.124.91
• 60 min/h)/(1000 mL/L) = 762 mg, rounded to 750 mg every 24 hours.
©2024 AMcGraw Hill. All
steadystate Rights
trough Reserved. serum
levetiracetam Termsconcentration
of Use • Privacy
canPolicy • Noticeafter
be measured • Accessibility
steadystate is attained in 35 halflives. Since the patient is
expected to have a halflife equal to 18.4 hours, the levetiracetam steadystate concentration could be obtained any time after the fourth day of
The Cl/F rate for a patient taking levetiracetam monotherapy and severe liver disease is 29.2 mL/min/1.73 m : Cl/F = [(29.2 mL/min)/(1.73 m )]
2.09 m2 = 35.3 mL/min. The estimated V/F would be ∼45 L, and the estimated halflife equals 18.4 h. SAUDI DIGITAL LIBRARY
Access Provided by:
For adults, the initial dose of levetiracetam is 1000 mg/d, administered every 24 hours for extendedrelease tablets. For patients with severe
liver disease, this dose is reduced by half to 500 mg every 24 hours. The dose is titrated up 5001000 mg/d every 23 weeks as needed, and the
patient is monitored for seizure frequency and adverse drug effects. The maximum dose is usually 30004000 mg/d for patients with normal
liver function, but these doses should be used with caution if severe liver disease is present.
Using linear pharmacokinetics, the new levetiracetam dose would equal: Dnew = (Cssnew/Cssold) Dold = (15 μg/mL/7.9 μg/mL) 2000 mg/d = 3797
mg/d, rounded to 4000 mg/d. The new dose is 2000 mg every 12 hours.
concentrations can be measured 35 halflives after the dosage change has been made (see Table 162: ∼t1/2 = 6.1 hours, ∼35 t1/2 in ∼12 days).
SteadyState OneCompartment Model Parameter Method
2. Use SteadyState OneCompartment Model Parameter Method to Compute a New Dose.
A. Compute the patient’s elimination rate constant and halflife (note: t′ = infusion time + waiting time of 15 minutes and ½ hour, respectively).

B. Compute
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of Use
C. Choose new steadystate trough concentration.

2. Use SteadyState OneCompartment Model Parameter Method to Compute a New Dose. Access Provided by:
A. Compute the patient’s elimination rate constant and halflife (note: t′ = infusion time + waiting time of 15 minutes and ½ hour, respectively).
B. Compute the patient’s volume of distribution.
C. Choose new steadystate trough concentration.
The desired steadystate trough concentration will be 15 μg/mL.
D. Determine the new dosage interval for the desired concentrations.
E. Determine the new dose for the desired concentrations.
The dose is computed using the onecompartment model intravenous bolus equation:
A dose of levetiracetam 2000 mg every 12 hours would be prescribed.
Bayesian Pharmacokinetic Computer Program
Patient is not at steadystate yet, and the levetiracetam concentration was obtained at middosage interval. These factors make it difficult to use
other methods to compute the best dose to achieve a target steadystate levetiracetam trough concentration.
1. Enter the patient's demographic, drugdosing, and serum concentration/time data into the computer program.
2. Compute pharmacokinetic parameters for the patient using Bayesian pharmacokinetic computer program.
The pharmacokinetic parameters computed by the program are a volume of distribution of 48 L, a halflife equal to 5.6 h, and a clearance equal
to 88 mL/min.
3. Compute dose required to achieve desired levetiracetam serum concentrations.
The onecompartment model firstorder absorption equations used by the program to compute doses indicates that a dose of 2000 mg every 24
hours will produce a steadystate levetiracetam trough concentration of 20 μg/mL.
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and 750mg tablets. J Clin Pharmacol. Dec 2003;43(12):1370–1376.
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pharmacokinetic profiles of warfarin. Epilepsy Res. Nov 2001;47(12):55–63.
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29. French J. Use of levetiracetam in special populations. Epilepsia. 2001;42(suppl 4):40–43.
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871.


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Applied Clinical Pharmacokinetics, 3e

2004 2013 Medical

2. Complex partial seizures (with Carbamazepine Lamotrigine Carbamazepine Adults:

3. Partial seizures evolving into Carbamazepine Lamotrigine Carbamazepine Adults:

Generalized seizures 1. Absence seizuresb (typical or Children:c Ethosuximide Ethosuximide Children:

Lamotrigine Lamotrigine Adjunctive: Lamotrigine

2. Tonic­clonic seizures (also known as Carbamazepine Valproate Carbamazepine Adults:

aOnly two highest available levels of evidence listed.

cLamotrigine added to previous recommendation per expert panel.

THERAPEUTIC AND TOXIC CONCENTRATIONS

CLINICAL MONITORING PARAMETERS

BASIC CLINICAL PHARMACOKINETIC PARAMETERS

BASIC CLINICAL PHARMACOKINETIC PARAMETERS

EFFECTS OF DISEASES AND CONDITIONS ON PHARMACOKINETICS AND DOSING

Test/Symptom Score 1 Point Score 2 Points Score 3 Points

Total bilirubin (mg/dL) <2.0 2.0­3.0 >3.0

Serum albumin (g/dL) >3.5 2.8­3.5 <2.8

Prothrombin time (seconds prolonged over control) <4 4­6 >6

Test/Symptom Score 1 Point Score 2 Points Score 3 Points

Total bilirubin (mg/dL) <2.0 2.0­3.0 >3.0

Serum albumin (g/dL) >3.5 2.8­3.5 <2.8

Prothrombin time (seconds prolonged over control) <4 4­6 >6

Ascites Absent Slight Moderate

Hepatic encephalopathy None Moderate Severe

INITIAL DOSAGE DETERMINATION METHODS

Pharmacokinetic Dosing Method

Clearance, Volume of Distribution, and Half­Life Estimates

Selection of Appropriate Pharmacokinetic Model and Equations

Selection of Appropriate Pharmacokinetic Model and Equations

1. Estimate creatinine clearance.

3. Compute dosage regimen.

1. Estimate creatinine clearance.

1. Estimate creatinine clearance.

3. Compute dosage regimen.

1. Estimate creatinine clearance.

3. Compute dosage regimen.

1. Estimate creatinine clearance.

3. Compute dosage regimen.

Literature­Based Recommended Dosing

>80 500­1500 mg every 12 h

50­80 500­1000 mg every 12 h

30­50 250­750 mg every 12 h

>80 500­1500 mg every 12 h

50­80 500­1000 mg every 12 h

30­50 250­750 mg every 12 h

<30 250­500 mg every 12 h

1. Estimate creatinine clearance.

1. Estimate creatinine clearance.

1. Estimate creatinine clearance.

1. Estimate creatinine clearance.

USE OF LEVETIRACETAM SERUM CONCENTRATIONS TO ALTER DOSES

Selection of Appropriate Pharmacokinetic Model and Equations

the dosage interval in hours.

Linear Pharmacokinetics Method

1. Compute new dose to achieve the desired serum concentration.

Pharmacokinetic Parameter Method

Pharmacokinetic Parameter Method

1. Compute pharmacokinetic parameters.

2. Compute the new levetiracetam dosage.

One­Compartment Model Parameter Method

Standard One­Compartment Model Parameter Method

2. Tonicclonic seizures (also known as Carbamazepine Valproate Carbamazepine Adults:

Total bilirubin (mg/dL) <2.0 2.03.0 >3.0

Serum albumin (g/dL) >3.5 2.83.5 <2.8

Prothrombin time (seconds prolonged over control) <4 46 >6

Total bilirubin (mg/dL) <2.0 2.03.0 >3.0

Serum albumin (g/dL) >3.5 2.83.5 <2.8

Prothrombin time (seconds prolonged over control) <4 46 >6

Clearance, Volume of Distribution, and HalfLife Estimates

LiteratureBased Recommended Dosing

>80 5001500 mg every 12 h

5080 5001000 mg every 12 h

3050 250750 mg every 12 h

>80 5001500 mg every 12 h

5080 5001000 mg every 12 h

3050 250750 mg every 12 h

<30 250500 mg every 12 h

OneCompartment Model Parameter Method

Standard OneCompartment Model Parameter Method

SteadyState OneCompartment Model Parameter Method

2. Use SteadyState OneCompartment Model Parameter method to compute a new dose.

c. Choose a new steadystate trough concentration.

2. Use SteadyState OneCompartment Model Parameter method to compute a new dose.

c. Choose a new steadystate trough concentration.

Downloaded 202443 9:49 P Your IP is 154.59.124.91

Literaturebased/concept Literaturebased Recommended Linear Pharmacokinetics method

LiteratureBased Recommended Dosing

LiteratureBased Recommended Dosing

LiteratureBased Recommended Dosing

LiteratureBased Recommended Dosing

LiteratureBased Recommended Dosing