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REVIEW ARTICLE
A Systematic Review of the Pharmacokinetics of Antiepileptic Drugs in
Neonates With Refractory Seizures
Joanie K. Tulloch, PharmD,1 Roxane R. Carr, PharmD,1,2 and Mary H.H. Ensom, PharmD1,2
1

Department of Pharmacy, Childrens and Womens Health Centre of British Columbia, Vancouver, British Columbia,
Canada; 2Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada

BACKGROUND Neonatal seizures are associated with neurological sequelae and an increased risk of
epilepsy later in life. Phenobarbital and phenytoin remain the antiepileptic drugs (AEDs) most commonly
used to treat neonatal seizures, despite their suboptimal effectiveness and safety. As a result, other AEDs,
such as levetiracetam and topiramate, are often used in neonates with refractory seizures, despite limited
data and off-label use.
OBJECTIVES To systematically review published pharmacokinetic data for second-line AEDs used in
neonates with seizures and to provide dosing recommendations for these agents in the neonatal
population.
METHODS A literature search was conducted in PubMed (1949-May 2012), Medline (1950-May 2012),
and Embase (1980-May 2012). Each study was ranked according to the quality of evidence it provided,
based on the classification system developed by the US Preventive Services Task Force. Information
extracted from each study included study design, number of subjects, gestational and postnatal age, AED
dosage regimen, pharmacokinetic parameters, pharmacokinetic model, AED serum concentrations, and
sampling times.
RESULTS Nineteen relevant pharmacokinetic studies involving a total of 8 different drugs were identified.
No prospective, randomized, controlled studies (level I evidence) or nonrandomized controlled studies
(level II-I evidence) were identified; 2 studies were prospective, nonrandomized, uncontrolled (cohort)
studies (level II-2 evidence), 11 studies obtained evidence from multiple time series (level II-3 evidence),
and 6 studies were case reports or descriptive studies (level III evidence).
CONCLUSIONS There are limited pharmacokinetic data for the use of carbamazepine, levetiracetam,
lidocaine, paraldehyde, topiramate, valproic acid, and vigabatrin for neonates with seizures refractory to
treatment with first-line antiepileptic agents. Further research is needed to elucidate target AED serum
concentrations (if any) required to optimize effectiveness and minimize dose-related adverse effects in
neonates.
INDEX TERMS anticonvulsants, antiepileptics, neonate, pharmacokinetics
J Pediatr Pharmacol Ther 2012;17(1):3144

INTRODUCTION
Neonatal seizures are associated with neurological sequelae (including motor and cognitive decits)
and an increased risk of epilepsy later in life.1 The
estimated incidence of neonatal seizures ranges from
1 to 3.5 cases per 1000 live births in term neonates
and from 58 to 132 cases per 1000 live births in
premature infants (,38 weeks postconceptual age).2
Despite the high incidence of seizures and potential

sequelae, there are currently no evidence-based

guidelines for the management of neonatal seizures.3
Phenobarbital, phenytoin, and benzodiazepines
remain the most common treatment modalities for
treating neonatal seizures.4 However, a randomized
controlled trial by Painter et al.5 comparing
phenobarbital and phenytoin as rst-line agents
for seizures in neonates found that greater than
50% of neonates treated with either phenobarbital
or phenytoin continued to have evidence of
abnormal electrical activity. When both phenobar-

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JK Tulloch, et al

Table 1. US Preventative Services Task Force11

Level of Evidence

Description

Evidence obtained from at least one properly randomized controlled trial

II-1

Evidence obtained from well-designed controlled trials without randomization

II-2

Evidence obtained from well-designed cohort or case-control analysis studies, preferably

from more than one center or research group

II-3

Evidence obtained from multiple time series with or without the intervention or
dramatic results in uncontrolled experiments

III

Opinions of respected authorities, based on clinical experience; descriptive studies and

case reports; or reports of expert committees

bital and phenytoin were administered together,

electrical control of seizures was achieved in only
60% of neonates. Furthermore, there is concern
regarding possible adverse effects of phenobarbital
and phenytoin on developing neuronal cells and
proliferation of cortical neurons.6 As a result, other
antiepileptic drugs (AEDs), such as levetiracetam
and topiramate, are used in neonates with refractory seizures despite limited data and off-label
use.3,7 The pharmacokinetics of AEDs in infants
and children has been reviewed previously.8-10
However, the limited pharmacokinetic data regarding the administration of AEDs in neonates are
provided in this review. Given the physiological
differences in neonates (including but not limited to
changes in gastric and intestinal pH, gastrointestinal motility, total body water-to-fat ratios, concentration and afnity of plasma binding proteins,
drug metabolizing enzyme activity, and renal
function), the pharmacokinetics of AEDs in this
patient population are expected to vary profoundly.10 This paper systematically reviews the published
pharmacokinetic data of second-line AEDs used in
neonates with seizures and provides dosage recommendations for these agents in the neonatal
population.

(rst-line treatments). The reference lists of all

relevant articles were manually searched for pertinent studies not identied in the electronic search.
Each study was ranked according to the quality
of evidence it provided based on the classication
system developed by the US Preventative Services
Task Force (Table 1).11 Information extracted from
each study (where available) included study design,
number of subjects, gestational and postnatal age,
AED drug regimen (i.e., drug, dosage, route,
duration), pharmacokinetic parameters (i.e., clearance and/or area under the concentration-time
curve [AUC], volume of distribution, and elimination half-life), pharmacokinetic model, AED drug
levels, and sampling times.
Nineteen relevant pharmacokinetic studies were
identied. No prospective, randomized, controlled
studies (level I evidence) or nonrandomized controlled studies (level II-1 evidence) were identied; 2
studies were prospective, nonrandomized, uncontrolled (cohort) studies (level II-2 evidence),25,26 11
studies obtained evidence from multiple time series
(level II-3 evidence),14-16,20,21,27,29,35,37,38,43 and 6
studies were case reports or descriptive studies (level
III evidence).22,30,39-42 The pharmacokinetic parameters reported for the 19 studies (7 drugs) are
summarized in Table 2.

LITERATURE SEARCH
A literature search was conducted in PubMed
(1949-2012), Medline (1950-May 2012), and Embase (1980-May 2012), using the following search
terms: neonate or newborn, anticonvulsant or
antiepileptic agent, and pharmacokinetics. The
search was limited to articles published in English
and using human subjects. Excluded were studies
describing the pharmacokinetics of AEDs in
neonates acquired from transplacental exposure
and studies describing the pharmacokinetics of
phenobarbital, phenytoin, or benzodiazepines
32

CARBAMAZEPINE
Carbamazepine prevents repetitive ring of
action potentials in depolarized neurons by blocking frequency, use, and voltage-dependent sodium
channels.12 It is currently available only as an oral
agent. An intravenous (IV) formulation has been
developed and is being studied in phase III clinical
trials. Carbamazepine is metabolized in the liver to
carbamazepine 10,11-epoxide (carbamazepine epoxide).9 Conversion is mediated primarily by
cytochrome (CYP) 3A4 (with minor metabolism

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1-7 mg/kg/hr (IV)

30 mg/kg/day (po)

3.8 6 2.2

250 mg/day (po)

1.21 (0.64-2.5)

Cpmax: 6.7 (3.2-9.9)

Cpss: 2.3-19.9
0.67 (0.09-0.85)

CL (mL/min/kg)*

Cpmax: NR
36.5 (35-38)
51.6 (35-78)
Cpss: 27-61 (po)

0.26 6 0.08

2 (0.74-4.7)

13.4 (7.7-28)

NR

NR

0.29 (0.24-0.36) 0.32 (0.1-0.48)

NR

1.73 (1.1-3.1)

Cpmax: 247 6 23
Cpmax: 17.96 6 4.2
Cpmin: 10.35 6 2.5

3.1 (3-3.2)

Cpmax: NR
Cpss: 5.74 (0.8-19)

Cpmax: 55 (14.8-91.9) 0.83 (0.37-1.26) 0.88 (0.43-2.89)

Cpss: 21 (11-31)

Vd (L/kg)*

Cp (mg/L)*

2.1 (0.6-3.2) 14 (7.3-20.8)

10-20 mg/kg/day (po) 1.5-3

NR
30 mg/kg/day (pr)
-

NR

6.8 (2-16)

Tmax (hr)*

7.5 (4.1-10.3)

21.7 (8.6-48.5)

35.6 6 19.3

10.2 (7.6-17.4)

5.3 (5.2-5.4)

13.2 (3.2-21)

14.2 (4.7-60.2)

T1/2 (hr)*

Cp, concentration; CL, clearance; Cpmax, maximum concentration achieved; Cpmin, minimum concentration achieved; Cpss, steady-state concentration; NR, not reported; IV, intravenous; IVF,
intravenous infusion; LD, loading dose; MD, maintenance dose; n, number of patients studied; po, oral administration; pr, rectal administration; PK, pharmacokinetic; Tmax, time to reach maximum
concentration; T1/2, half life; Vd, volume of distribution
* Data are means 6 SD or SEM (range)

6 125 mg (po)

12 20-25 mg/kg (po)

20-30 mg/kg (pr)
10-25 mg/kg (IV)

Valproic Acid

Vigabatrin

13 5 mg/kg (po)

MD (route)
9-21 mg/kg/day (po)

9 150 mg/kg/hr 3 3 hr (IVF) -

120 1.5-2.2 mg/kg (IVF)

Topiramate

Paraldehyde

Lidocaine

23 14.4-40 mg/kg (IV)

60 mg/kg (po)

Levetiracetam

LD (route)

22 5-20 mg/kg (po)

Carbamazepine

Drug

Dosage Studied

Table 2. Summary of Dosages and Pharmacokinetic Parameters

Pharmacokinetics of Antiepileptics in Neonates

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by CYP1A2 and CYP2C8). The active epoxide

metabolite is hydrolyzed to an inactive diol
metabolite that is renally eliminated. Furthermore,
carbamazepine is known to induce its own metabolism through the epoxide-diol pathway. This
appears to be a dose-related mechanism with onset
as early as 24 hours and time to completion ranging
from 1 to 5 weeks. Steady-state concentrations are
therefore lower than those predicted from singledose studies.13
Level II-3 Evidence
Singh et al14 evaluated the pharmacokinetics of
carbamazepine monotherapy (Tegretol syrup; CibaGeigy Corp., Summit, New Jersey) in 10 term
neonates. A loading dose of carbamazepine (10 mg/
kg) was administered via a nasogastric tube in 10
consecutive neonates experiencing two or more
seizures. Serum drug concentrations were drawn at
1, 2, 4, 8, 12, and 24 hours following the loading
dose in the rst 5 neonates and at 4, 8, 12, 16, 20,
and 24 hours in the latter 5 patients. The
pharmacokinetic model used to describe the data
not reported.
Carbamazepine serum concentrations reached
acceptable therapeutic range for older children (49.8 mg/L) within 2 hours in the rst 5 neonates
and within 4 hours (the time of rst measurement)
in the latter 5 neonates. A reference for this
therapeutic range was not provided. Peak concentrations were achieved 4 to 16 hours after the oral
loading dose and ranged from 7.1 to 9.9 mg/L. The
elimination half-life ranged from 9.6 to 60.2 hours
(mean, 24.5 hours). Maintenance therapy was
initiated 24 hours after the loading dose, with a 7
mg/kg dose administered orally every 8 hours in the
rst 5 neonates and a 5 mg/kg dose administered
orally every 8 hours in the latter 5 neonates. Serum
drug concentrations ranged from 7.0 to 19.9 mg/L
in the rst 15 days. A decrease in carbamazepine
serum concentration of between 2.3 and 4.8 mg/L
was noted between day 8 and day 15 of maintenance therapy. No information was provided
regarding the timing of the serum concentrations
in relation to the dose.
Rey et al15 evaluated the pharmacokinetic
parameters of carbamazepine following administration of a single oral dose (15-20 mg/kg) of crushed
carbamazepine tablets to 6 neonates (gestational
age not reported). Serum drug concentrations were
drawn over the next 48 hours after administration
of the dose. Pharmacokinetic parameters were
derived using a 1-compartment model. Peak serum
carbamazepine concentrations were achieved 2.3 to
6.8 hours after administration of the single oral
dose. Concentrations ranged from 5.8 to 9 mg/L.
34

The elimination half-life ranged from 4.7 to 11.3

hours (mean, 7.8 hours).
MacKintosh et al16 evaluated the pharmacokinetics of carbamazepine in 6 neonates following
administration of a smaller single oral dose (5 mg/
kg) of carbamazepine suspension (prepared by the
pharmacy at the institution). Serum drug concentrations were drawn at 2, 4, 6, 8, and 12 hours
following the one dose. The pharmacokinetic model
used to describe the data was not reported.
Peak serum concentrations were achieved 2 to 12
hours following administration of the carbamazepine dose with concentrations ranging from 3.2 to
5.3 mg/L. The elimination half-life ranged from 7.2
to 14.5 hours (mean, 10.3 hours). Maintenance
therapy was then initiated with a 5 mg/kg dose
administered orally every 12 hours, with doses
adjusted as necessary to maintain serum concentrations between 2.4 and 9.6 mg/L. Subsequent
trough serum concentrations (12 hours after the
preceding dose) were monitored 3 to 15 days after
initiating therapy. Five of the 6 neonates attained
trough carbamazepine serum concentrations within
the targeted therapeutic range with doses ranging
from 4.6 to 8.1 mg/kg/dose administered every 12
hours.
Dosage Considerations
In neonates, limitations to the use of carbamazepine include (1) lack of a parenteral formulation;
(2) low activity of isoenzyme CYP 3A4 at birth,
increasing to approximately 20% of adult values at
1 month of age (although whether this impacts
effectiveness is unknown); (3) epoxide hydrolase
enzymes not fully developed and functioning; and
(4) reduced renal elimination (potentially decreasing clearance of carbamazepine and the epoxide
metabolite).17
Given the above-described limitations, determining an ideal carbamazepine dose for neonates is
difcult. Initial loading doses studied ranged from 5
to 20 mg/kg and maintenance doses from 5 to 8 mg/
kg/dose administered every 8 to 12 hours (9-21 mg/
kg/day), with wide variations in serum concentrations.14-16 Singh et al14 noted a decrease in serum
carbamazepine concentrations ranging from 2.3 to
4.8 mg/L between days 8 and 15 of maintenance
therapy, with a more gradual decline noted over the
next 3 months of therapy (specic values not
provided). Increases in drug metabolizing capacity,
which generally occurs (in a term neonate) around 1
week of life, likely explain the signicant drop in
serum concentrations.18 The continual decline in
serum concentrations is most likely due to both
autoinduction and continued maturation of CYP
P450 enzymes in the neonate. However, it is

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important to note that for the neonatal population,

the desired reference range for carbamazepine
(dened as the range of drug concentrations
specifying a lower limit below which a therapeutic
response is unlikely to occur and an upper limit
above which toxicity is likely to occur) is not
known.19
Practitioners must also be aware of drug
interactions with carbamazepine. Rey et al15 and
MacKintosh et al16 reported a signicantly shorter
mean elimination half-life of carbamazepine in
neonates (7.8 and 10.3 hours, respectively) than
Singh et al14 did (24.5 hours).This may be explained
by enzyme induction by interacting medications,
primarily phenobarbital and phenytoin. Five of the
6 neonates studied by MacKintosh et al16 received
phenobarbital and/or phenytoin prior to treatment
with carbamazepine, while all 6 neonates studied by
Rey et al15 were receiving concomitant phenobarbital therapy; the neonates studied by Singh et al14
were treated with carbamazepine monotherapy as a
rst-line agent.

LEVETIRACETAM
Levetiracetam is the active, water-soluble Senantiomer of racemic pyrrolidine acetamide. It is
believed to act by a nonconventional mechanism,
binding to the synaptic vesicle protein within the
brain.21 In the United States, levetiracetam is
available both as an oral and as an IV agent. In
Canada, it is currently available only in the oral
form. Levetiracetam is not bound to plasma
proteins.19 Unlike other AEDs that are metabolized, the metabolism of levetiracetam does not
include the CYP P450 system. Two-thirds of the
dose is eliminated unchanged in the urine while
approximately one-third is hydrolyzed in the blood
and various tissues into 3 inactive metabolites that
are renally excreted.19
Level II-3 Evidence
Merhar et al20 prospectively evaluated the
pharmacokinetic of levetiracetam following the
administration of a single IV loading dose in 19
neonates (both term and preterm). Three serum
drug concentrations were collected in each patient
(times not specied). A non-linear xed effects
model was used to analyze the pharmacokinetic
data with a 2-compartment model with rst order
elimination used to describe the data. Individual
Bayesian pharmacokinetic parameter estimates
were then used to determine the pharmacokinetic
parameters for each neonate. The loading dose of
levetiracetam was chosen by the prescribing physician and ranged from 14.4 to 39.9 mg/kg. Peak
serum concentrations (1 hour after the loading

dose) ranged from 14.8 to 91.9 mg/L (median, 39.8

mg/L). The median volume of distribution was 0.89
L/kg, median clearance 1.21 mL/min/kg and
median elimination half-life 8.9 hours. Blonk et
al21 evaluated the pharmacokinetics of levetiracetam in 2 neonates with seizures refractory to a total
dose of 40 mg/kg of phenobarbital and 0.5 mg/kg of
midazolam (total dose). Levetiracetam was administered by IV route at a dose of 20 mg/kg over 5
minutes. In case of continuing seizures, an additional 20 mg/kg dose of levetiracetam was administered approximately 10 minutes after the end of
the rst infusion. Serum concentrations were drawn
at 5, 15, 20, 30, and 60 minutes and at 2, 4, 8, 12, 24,
36, 48, 60, and 78 hours after the start of infusion.
A 3-compartment pharmacokinetic model was used
to describe the data.
A linear concentration-time prole was obtained, with a peak serum concentration of approximately 70 mg/L in each neonate following the
administration of a total IV dose of 40 mg/kg of
levetiracetam. Mean volume of distribution was
0.76 L/kg, mean clearance was 0.53 mL/min/kg,
and mean elimination half-life was 17.5 hours. Both
neonates required an additional dose of levetiracetam, 20 mg/kg, for continuing seizures 10 minutes
after the end of the rst infusion (total dose of 40
mg/kg). The clinical outcomes of the 2 neonates
were not reported.
Level III Evidence
A case series described the pharmacokinetics of
levetiracetam in 2 neonates who had received oral
levetiracetam for the treatment of refractory seizures.22 A 42-week gestational neonate was administered a levetiracetam bolus (60 mg/kg) via an
orogastric tube after phenobarbital and phenytoin
failed to control the patients seizures. Clinical and
electroencephalographic (EEG) cessation of seizures were reported within 17 minutes of the
levetiracetam bolus. The neonate was maintained
on a dosage of 30 mg/kg/day. A trough concentration at discharge was 31 mg/L (the reference range
in adults is 10-40 mg/L).19 A second neonate, born
at 26 weeks gestation, developed seizures on day 5
of life. Levetiracetam was administered via orogastric tube at a dosage of 30 mg/kg/day following
inadequate seizure control with fosphenytoin. A
levetiracetam trough concentration 1 week after
therapy was initiated was 11 mg/L. At 1 year of life,
the infant remained seizure free on levetiracetam
monotherapy and showed normal EEG results.
Dosage Considerations
The availability of an IV formulation (in the
United States), excellent oral bioavailability (as

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described in adults),19 lack of plasma protein

binding, and CYP P450-independent metabolism
make levetiracetam an attractive antiepileptic agent
for use in neonates. Unfortunately, very little
information has been published about the pharmacokinetics of levetiracetam in the neonatal population. Doses reported in the neonatal population
range from loading doses of 15 to 60 mg/kg and
maintenance dosages of 30 mg/kg/day, which are
similar to the dosages used in infants and older
children.23 However, the increased volume of
distribution of levetiracetam reported in neonates,20
may indicate that neonates require a larger loading
dosing than adults and older children. Furthermore, given the fact that renal function affects the
rate of elimination of levetiracetam, the elimination
half-life of levetiracetam would be expected to be
prolonged in neonates and even further prolonged
in preterm neonates, given their immature renal
function. Further studies should be conducted to
investigate the use levetiracetam in neonatal seizures in order to establish efcacy and safety and to
help guide dosing.

LIDOCAINE
Lidocaine, an amide local anesthetic, has a
concentration-dependent effect on seizures. At
lower concentrations, lidocaine can effectively
suppress clinical and electrographic manifestations
of seizures. However, at higher concentrations, it
may cause seizures. The mechanism mediating this
proconvulsant effect is not completely understood.24 When used for treating seizures, lidocaine
is administered by continuous IV infusion due to its
short half-life (90-100 minutes). Lidocaine is 60%
to 80% bound to alpha1-acid glycoprotein. It is
metabolized primarily by the liver (90%) into two
active metabolites, monoethylglycinxylidide and
glycinxylidide, which are excreted renally. These
active metabolites are thought to contribute both to
efcacy in terminating seizures as well as to toxicity
in provoking seizures.19
Level II-2 Evidence
Hellstrom-Westas et al25 prospectively studied
24 neonates (14 term and 10 preterm) with seizures
refractory to phenobarbital. Twenty-one neonates
had also received diazepam and/or phenytoin when
treatment with phenobarbital alone had failed.
Lidocaine treatment was initiated on postnatal
days 0 to 16, with an IV loading dose of 1.5 to
2.2 mg/kg followed by an initial maintenance
infusion of 4 to 6 mg/kg/hour. Blood concentrations of lidocaine and its active metabolites (monoethylglycinxylidide and glycinxylidide) were
measured at 30 minutes and at 1, 2, 4, 8, 12, 24,
36

48 and 72 hours after initiation of the lidocaine

infusion and was repeated every 24 hours during the
infusion. The pharmacokinetic model used in the
studies to describe the data was not reported.
The mean duration of the lidocaine infusion was
74.3 hours (range, 2-233 hours) in term infants and
105.2 hours (range, 22-144 hours) in preterm
infants. Within 10 hours of infusion, mean lidocaine
concentrations were above 6 mg/L, the upper limit
of the reference range reported in adults (when it is
used for antiarrhythmic therapy), and within 24
hours a signicant accumulation of lidocaine (mean
concentration, 19 mg/L) and monoethylglycinxylidide (mean concentration, 9 mg/L) was noted. No
signicant difference in blood concentrations of
lidocaine (or its active metabolites) was found
between term and preterm neonates or between
neonates who responded (seizures stopped) to the
lidocaine infusion and those who had no anticonvulsant response. After the lidocaine infusion was
discontinued, both lidocaine and its active metabolites were eliminated within 24 to 48 hours in all
neonates. No other pharmacokinetic parameters
were reported.
Rey et al26 prospectively studied 13 neonates (8
term, 5 preterm) who began receiving lidocaine
infusion after phenobarbital and diazepam therapy
failed to control seizures. Lidocaine was infused at a
rate of 4 mg/kg/hour on day 1 of therapy. The
infusion rate was decreased by 1 mg/kg/hour per
day and discontinued on day 5. Lidocaine plasma
concentrations were monitored every 12 to 24
hours. The pharmacokinetic model used to describe
the data was not reported.
Mean lidocaine concentrations in preterm and
term neonates 24 hours after the start of the 4 mg/
kg/hour infusion were 8.2 mg/L (3-10.5 mg/L) and
4.5 mg/L (2.8-7 mg/L), respectively. Assuming
steady-state was achieved at least 24 hours after
the start of infusion (based on a lidocaine elimination half-life of 3.16 hours, previously reported
following subcutaneous administration of lidocaine
in 4 neonates),24 clearance was calculated for each
infusion rate in both preterm and term neonates.
Clearance was signicantly lower in preterm neonates for all dose rates. In both term and preterm
infants, lidocaine clearance increased with decreased infusion rates, suggesting lidocaine elimination is a saturable process.
Level II-3 Evidence
Malingre et al27 studied 20 neonates treated with
IV lidocaine following inadequate seizure control
with phenobarbital (with or without a benzodiazepine). An IV loading dose of lidocaine 2 mg/kg
was administered over 10 minutes, followed by a

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continuous infusion of 6 mg/kg/hour for 12 hours, 4

mg/kg/hour for 12 hours, and 2 mg/kg/hour for 12
hours. Plasma samples were drawn at 8, 12, 24, 36,
50, and 72 hours after the start of the infusion. A 1compartment model was used to describe the data.
Thirteen neonates (65%) had lidocaine plasma
concentrations greater than 9 mg/L at some point
during the infusion (time not-specied). Plasma
concentrations above 9 mg/L have been associated
with cardiac toxicity in adult patients.28 The mean
clearance and volume of distribution of lidocaine
were estimated to be 10.7 mL/min/kg and 3.2 L/kg,
respectively.
In a second phase of their study, Malingre et al27
developed a new lidocaine infusion regimen to
reduce the risk of toxicity in neonates. The modied
lidocaine infusion regimen (2 mg/kg IV loading
dose over 10 minutes, followed by a continuous IV
infusion of 6 mg/kg/hour for 6 hours, 4 mg/kg/hour
for 12 hours, and 2 mg/kg/hour for 12 hours) was
then administered to 15 neonates. The new regimen
resulted in lidocaine plasma concentrations less
than 9 mg/L in 11 of the 16 neonates (73%). Five
neonates (3 preterm, gestational age 27-33 weeks)
continued to have plasma concentrations greater
than 9 mg/L. Cardiac toxicity was not observed
with either regimen.
In an attempt to reduce the risk of lidocaine
toxicity in preterm neonates, Van den Broek et al29
developed a new lidocaine infusion regimen for
term and preterm neonates by using population
pharmacokinetic modeling and simulation. Van den
Broek et al used the infusion regimen previously
described by Malingre et al27 in 46 neonates
(including 18 preterm neonates) within 10 days of
birth. Plasma lidocaine concentrations were collected after completion of the initial lidocaine loading
dose (2 mg/kg), during the dose-reduction steps,
and in cases of (suspected) toxicity. These concentrations were then used to create a pharmacokinetic
model able to predict individual and population
lidocaine concentration-time proles for neonates
with different body weights and maturation progress.
The dosing strategy developed consists of an
initial bolus dose of 2 mg/kg (administered over 10
minutes), followed by a body weight-based infusion
over 4 hours, with different doses for different
weight categories (0.8-1.5 kg, 5 mg/kg/hour over 4
hours; 1.6-2.5 kg, 6 mg/kg/hour over 4 hours; 2.64.5 kg, 7 mg/kg/hour over 4 hours). After the 4hour infusion was completed, the infusion is
reduced to half the initial infusion rate for 6 hours
and then further reduced by half for an additional
12 hours.
Using the dosage regimen described by Malingre
et al27, 31% of neonates had lidocaine plasma

concentrations of .9 mg/L following the 6-hour

infusion. Using this new dosing strategy, the
median concentration achieved at the end of the
4-hour infusion was 6.1 mg/L with only 2.4% of the
simulated individual plasma concentrations greater
than 9 mg/L. Prospective validation of this infusion
regimen is currently under study.
Level III Evidence
Wallin et al30 published a case series of 3
neonates with refractory seizures treated with IV
lidocaine for 3 days, 3 weeks, and 3 months,
respectively. One term neonate, 2 days postnatal
age, receiving lidocaine infusion (6.8 mg/kg/hour
for the rst 12 hours) after phenobarbital and
diazepam failed to control seizures. Within 12
hours, plasma concentrations of lidocaine and
monoethylglycinxylidide were 13.6 mg/L and 2.6
mg/L, respectively; glycinxylidide was not detected
until 36 hours after the infusion was started. After
the lidocaine infusion was stopped after 3 days of
treatment, the estimated plasma half-life of lidocaine and monoethylglycinxylidide was 5.2 hours
and 28.4 hours, respectively. Similarly, the second
case report describes a term neonate successfully
treated with IV lidocaine for 3 weeks (average daily
dosage: 2 mg/kg/hour). The plasma concentration
of lidocaine after 1 week of infusion was 1.6 mg/L.
Plasma concentrations were not reported for the
third neonate. Two infants (treated for 3 weeks and
3 months, respectively) experienced repeated seizures when the lidocaine dose was decreased (in an
attempt to wean from the lidocaine infusion). The
authors speculated that these seizures were due to
the accumulation of monoethylglycinxylidide and
glycinxylidide, which increased the excitability of
the nervous system while the inhibitory effect of the
parent compound was reduced.30
Dosage Considerations
There are pharmacokinetic data to support the
use of lidocaine infusions in neonates with refractory seizures; however, signicant concern exists
regarding the toxicities of lidocaine. In neonates,
the volume of distribution and unbound fraction of
lidocaine are expected to be greater than in adults
given the reduced concentration of plasma proteins
in neonates. Lower glomerular ltration rates will
result in decreased renal clearance of lidocaine and
its active metabolites, thereby increasing the risk of
toxicity when used for prolonged periods in
neonates.31 As such, the lidocaine infusion regimen
proposed by Malingre et al27 is not recommended
for use in premature neonates, based on poor
response and high lidocaine plasma concentrations
reported in the four preterm neonates (gestational

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JK Tulloch, et al

age, 27-33 weeks). The infusion regimen proposed

by Van den Broek et al29 is promising but requires
validation before it can be recommended (Table 2).

relationship between dose and serum concentration.

Approximately 70% of the drug is eliminated
unchanged in the urine.19,37

PARALDEHYDE

Level II-3 Evidence

One trial investigating the pharmacokinetics of
topiramate in neonates was identied.37 In that
study, 13 full-term neonates with hypoxic ischemic
encephalopathy were randomized to receive either
deep (30-338C) or mild (33-348C) hypothermia.
Topiramate was administered to all neonates via
orogastric tube as enteric-coated granules mixed
with water at a dose of 5 mg/kg once per day for the
rst 3 days of life. Seven of the 13 neonates received
concomitant treatment with phenobarbital. Topiramate plasma concentrations were evaluated for
the rst 9 patients after 48 hours of hypothermia,
before the third dose of topiramate was administered (at 48 hours) and over the next 24 hours. The
nal 4 patients had topiramate plasma concentrations drawn at the beginning of hypothermia (at 0
hours) and over the next 72 hours. A noncompartmentmental pharmacokinetic model was used to
describe the data.
Topiramate plasma concentrations were within
the stated reference range of 5 to 20 mg/L in 11 of
the 13 neonates who were cooled for 72 hours. This
reference range was extrapolated from adult data.19
Peak plasma concentrations were achieved at 3.8 6
2.2 hours after oral topiramate administration and
ranged from 15.38 to 19.87 mg/L. The mean volume
of distribution was not reported. The mean
clearance was 0.26 mL/min/kg, and the mean
elimination half-life was 35.6 6 19.3 hours. The
pharmacokinetic parameters between the neonates
treated with deep and mild hypothermia did not
differ signicantly. Neonates who were treated with
phenobarbital (an enzyme inducer) had a signicantly lower minimum plasma concentration
(Cp min ) than those given topiramate alone
(p0.032); however, none of the other pharmacokinetic parameters differed signicantly.

Paraldehyde, a polymer of acetaldehyde, has been

used historically as a sedative-hypnotic and for
refractory seizure control, but its exact mechanism
of action is unclear.32 It is primarily metabolized via
the CYP P450 system and is partially excreted through
the lungs.33 Paraldehyde is available as an IV solution
(AFT Pharmaceuticals Ltd., Auckland, New Zealand); however, IV paraldehyde is not commonly used
to treat neonatal seizures. Serious adverse effects,
including pulmonary edema, pulmonary hemorrhage,
and hypotension have been reported in older children
after IV administration of paraldehyde.34 In North
America, paraldehyde is administered primarily
rectally to treat refractory seizures, despite limited
evidence to support this practice.
Level II-3 Evidence
One trial describing the pharmacokinetics of IV
paraldehyde in the treatment of neonatal seizures
was identied.35 Nine term neonates with status
epilepticus (dened as repeated clonic or tonic
convulsions lasting longer than 1 hour) refractory
to phenobarbital and phenytoin were given paraldehyde IV infusion (150 mg/kg/hr) for 3 hours.
Blood samples were collected prior to initiation of
therapy, hourly during the infusion, and at 1, 3, 6, 9,
21, 33, and 45 hours after completion of the
infusion. A 1-compartment pharmacokinetic model
was used to describe the data. Mean peak paraldehyde concentration achieved was 247 mg/L, mean
volume of distribution was 1.73 L/kg, mean
clearance was 0.121 L/hr/kg, and mean elimination
half-life was 10.2 hours.
Dosage Considerations
The pharmacokinetic data for IV paraldehyde
are limited in neonates with refractory seizures.
Furthermore, concern regarding signicant adverse
effects of IV paraldehyde in older children limits its
use. No pharmacokinetic data regarding rectal
paraldehyde in neonates are available to help guide
dosing.34,36

TOPIRAMATE
Topiramate is an AED with multiple mechanisms of action, including glutamate receptor
inhibition and sodium blockade. It is currently
available only as an oral formulation. Topiramate is
not highly protein bound and exhibits a linear
38

Dosage Considerations
Limited pharmacokinetic data are currently
available to guide the dosage regimen of topiramate
in neonatal seizures. The dosage regimen used by
Filippi et al37 (topiramate 5 mg/kg orally once
daily) achieved plasma concentrations within the
commonly reported reference range of 5 to 20 mg/
L. This dose regimen, however, was developed
arbitrarily with the purpose of rapidly achieving
therapeutic plasma concentrations for a short
period of time (3 days) in this select patient
population. Given the long half-life (35.6 hours)
of topiramate in that study, it would be expected

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Pharmacokinetics of Antiepileptics in Neonates

that steady-state topiramate concentrations would

be much higher than the values achieved in this
study. Data for the pharmacokinetics of topiramate
in normothermic neonates are limited to newborns
of mothers treated with topiramate. Further pharmacokinetic studies investigating the dosing of
topiramate in neonates in normothermic conditions, over a longer period of time are needed before
we can make dosing recommendations.

hours until individualized pharmacokinetic calculations allowed for dose adjustments to attain a
targeted trough concentration between 40 and 50
mg/L. Valproic acid controlled seizures in 5 of the 6
neonates, with trough concentrations reported
between 26 and 60 mg/L. Although serum ammonia
levels were elevated in all 6 of the neonates treated
with valproic acid, hyperammonemia led to the
discontinuation of valproic acid in 3 (50%) of the
neonates.

VALPROIC ACID
The mechanism of action of valproic acid
(Depakene syrup) is not completely understood. It
acts on a variety of targets, including sodium
channel blockade, increased c-aminobutyric acid
(GABA) function, and modulation of N-methyl-Daspartate (NMDA) receptors.10,19 Valproic acid is
available both as an oral and an IV agent. Like
phenytoin, valproic acid is highly (90%-95%)
protein bound (primarily to albumin). However,
the protein binding of valproic acid is saturable,
resulting in a nonlinear increase in free drug
concentration with dose escalation, and, in patient
populations with lower concentrations of serum
binding proteins,19 valproic acid is primarily
metabolized in the liver by b-oxidation (30%) and
glucuronidation (40%). Its metabolites are excreted
renally.
Level II-3 Evidence
Gal et al38 evaluated the pharmacokinetics of
valproic acid administered orally to 6 neonates with
prolonged, intractable seizures, who were unresponsive to phenobarbital used in conjunction with
at least one other anticonvulsant (phenytoin,
lorazepam, and/or paraldehyde). A loading dose
of valproic acid (20-25 mg/kg) was administered via
nasogastric tube, and serum valproic acid concentrations (both total and free) were measured 4 times
over a 12-hour period. Pharmacokinetic parameters
were derived using a 1-compartment model.
Peak concentrations (Cmax) were not reported,
whereas time to peak concentration (Tmax) was
stated to have occurred within 2 to 3 hours of the
initial oral dose. Large interpatient differences were
noted in the volume of distribution, apparent oral
clearance, and elimination half-life of both total
(0.36-0.46 L/kg, 5.5-28.9 mL/hr/kg, and 8.6-36.3
hours, respectively) and free (1.41-2.44 L/kg, 42-252
mL/hr/kg, and 6.7-14.5 hours, respectively) valproic
acid concentration. The free fraction ranged from
11.3% to 31.6% (mean, 19.2%) with the free
fraction increasing with total serum valproic acid
concentrations. All patients were given a maintenance dose of 5 to 10 mg/kg valproic acid every 12

Level III Evidence

Steinberg et al39 reported two case studies in
which rectal valproic acid successfully terminated
refractory neonatal seizures. Total serum concentrations of 35 and 38 mg/L were attained after rectal
administration of valproic acid syrup in doses of 20
mg/kg and 30 mg/kg, respectively. The relation of
these concentrations to the timing of the dose was
not specied.
Irvine-Meek et al40 described the pharmacokinetic parameters of valproic acid following the
administration of a single oral dose (7.5 mg/kg) of
valproic acid syrup in a 24-day old neonate.
Pharmacokinetic parameters were derived using a
1-compartment model. The volume of distribution
was 0.28 L/kg, apparent oral clearance 0.18 mL/
min/kg, and elimination half-life 17.2 hours.
Last, Alfonso et al41 published two additional
case studies in which 2 neonates with seizures
refractory to phenobarbital and phenytoin were
treated with IV valproic acid. Serum valproic acid
concentrations were measured 15 minutes and 2.5
hours following a 30-minute loading dose infusion.
Each 1 mg/kg IV valproic acid increased the 15minute and 2.5-hour postinfusion total serum
valproic acid concentrations by 4 and 3 mg/L,
respectively. The calculated volume of distribution
and clearance of valproic acid were 0.245 L/kg and
25 mL/hr/kg, respectively.
Dosage Considerations
Limited pharmacokinetic data are currently
available to guide dosages of IV and/or rectal
administration of valproic acid in neonatal seizures.
Initial loading doses studied ranged from 20 to 25
mg/kg (oral), 20 to 30 mg/kg (rectal), and 10 to 25
mg/kg (IV); maintenance dosages ranged from 5 to
10 mg/kg/dose (oral) and 15 mg/kg/dose (rectal)
administered every 12 hours, with wide variations in
serum concentrations. Like other AEDs, dosing
must be based on patient response (efcacy and
safety) and not on valproic acid concentrations as
the therapeutic range for valproic acid in
neonates is unknown. Further studies are required

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39

40

IV Infusion

Oral
IV (US)

Levetiracetam

Lidocaine

Oral

Route of Administration

Carbamazepine

AED

Significant toxicities associated

with prolonged infusions/high
serum concentrations (e.g.,
CNS, seizures; CVS,
arrhythmias)

Avoid using for prolonged periods; there is an

increased risk of toxicity because of decreased
renal elimination of lidocaine and its active
metabolites

2.6-4.5 kg: 7 mg/kg/hour for 4 hr, then 3.5

mg/kg/hr for 6 hr, then 1.75 mg/kg/hr for 12
hr;

then 1.5 mg/kg/hour for 12 hr;

1.6-2.5 kg: 6 mg/kg/hr for 4 hr, then 3 mg/

kg/hr for 6 hr,

0.8-1.5 kg: 5 mg/kg/hr for 4 hr, then 2.5

mg/kg/hr for 6 hr, then 1.25 mg/kg/hr for 12
hr;

Dosage: 2 mg/kg (infused over 10 min),

followed immediately by infusion based on the
following weight categories:

LD: 40-60 mg/kg;

MD: 30 mg/kg/day;
Requires dosage adjustment in renal failure

Limited PK data in neonates to

guide dosing

Available as an IV agent (US);

100% bioavailability;
No protein binding;
CYP P450- independent
metabolism;
No drug interactions (e.g.,
phenytoin, phenobarbital)
Multiple PK studies in neonates
to help guide dosing (e.g., 2
level II-2, 2 level II-3, and 1
level III study);

LD: 5-20 mg/kg;

MD: 5-8 mg/kg/dose every 8-12 hr (9-21 mg/
kg/day);
Because of cytochrome P450 enzyme
maturation and autoinduction (peak effect 8
to 15 days after initiation) as neonates age,
dosage increases will be necessary over the first
3 months of therapy to maintain target serum
concentrations

Dosage Guidelines and Considerations

No IV formulation;
Autoinduction (challenging to
dose);
Drug interactions (e.g., with
phenytoin, phenobarbital)

Disadvantages

3 (level II-3) PK studies to help

guide dosing

Advantages

Table 3. Summary of Advantages, Disadvantages, and Dosing Guidelines and Considerations

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Oral

Oral
PR
IV (US)

Oral

Topiramate

Valproic acid

Vigabatrin

Wide therapeutic index;

Not protein bound;
Not metabolized

Multiple routes of
administration

Partially excreted via the lungs

(excretion not limited in
neonates)

Advantages

Loading dose:
20 to 25 mg/kg (po)
20 to 30 mg/kg (pr)
10 to 25 mg/kg (IV);
Maintenance dose:
5-10 mg/kg/dose every 12 hr (po)
15 mg/kg/dose every 12 hr (pr);
Liver function and ammonia levels must be
monitored;
Enzyme-inducing medications (e.g.,
phenobarbital, phenytoin) should be
discontinued while administering valproic acid
(to minimize risk of hepatotoxicity)
Insufficient data to recommend dosage
guidelines for neonates
No IV formulation;
Limited PK data in neonates;
50% efficacy when used for
refractory neonatal seizures

Neonates receiving therapeutic hypothermia: 5

mg/kg once daily;
No data to guide dosing in normothermic
neonates or neonates receiving therapeutic
hypothermia for more than 3 days

IV paraldehyde should not be used to treat

refractory neonatal seizures given the risk of
significant adverse effects;
No data to guide PR dosages in neonates

Dosage Guidelines and Considerations

Saturable protein binding;

Associated with fatal
hepatotoxicity and
hyperammonemia;
Children ,2 years of age are at
increased risk;
Limited PK data to guide IV/PR
dosages of valproic acid in
neonates

No IV formulation currently
available;
PK data in neonates are limited
to neonates being cooled

IV route is associated with

significant adverse effects
(pulmonary edema, pulmonary
hemorrhage, hypotension);
Rectal route: no PK studies in
neonates

Disadvantages

AED, antiepileptic drug; CNS, central nervous system; CVS, cardiovascular system; IV, intravenous; LD, loading dose; MD, maintenance dose; PK, pharmacokinetic; PR, rectal route

IV
Rectal

Route of Administration

Paraldehyde

AED

Table 3. Summary of Advantages, Disadvantages, and Dosing Guidelines and Considerations (cont.)

Pharmacokinetics of Antiepileptics in Neonates

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to determine the optimal oral, rectal and IV dosing

of valproic acid in the neonatal population.

vigabatrins effectiveness in neonatal seizures is

required.

VIGABATRIN

SUMMARY

Vigabatrin, a selective inhibitor of GABA

transaminase, increases GABA (a major inhibitory
neurotransmitter) concentrations in the central
nervous system. It is administered orally as a
racemic mixture of two enantiomers, S() and
R(); only the S() enantiomer is pharmacologically active.19 Vigabatrin is not protein bound and
exhibits linear kinetics. It is not metabolized and is
primarily excreted unchanged in urine.

Table 3 summarizes the overall advantages and

disadvantages of each of the 7 second-line AEDs
that have pharmacokinetic data in neonates and
provides dosing considerations and guidelines for
use in neonates. In summary, the pharmacokinetics
of AEDs are impacted by age.1 While seizures occur
more often in the neonatal period than at any other
time in life,2 there are limited pharmacokinetic data
to guide the dosages for AEDs in this population.
The available pharmacokinetic data are derived
primarily from small, nonrandomized, noncontrolled trials, case studies, and retrospective reviews.
This information is difcult to apply in clinical
practice as limited data are provided (about the
patient, how the drug was administered, the timing
of drug levels, the clinical outcome, and other data).
Many of the studies include both term and preterm
neonates, who differ in their physiological development and ability to eliminate drugs, accounting for
some of the variability in the reported pharmacokinetic parameters.
The neonate, whether term or preterm, is rapidly
developing during the rst month of life. Administering drug dosages at steady state likely does not occur
for many of the AEDs, given the neonates rapid and
ongoing organ developement.44 As a result, the
neonatal patient receiving AEDs must be continually
monitored and drug doses adjusted based on clinical
parameters and physiological development. While
established reference ranges of AEDs do not necessarily apply to the neonate, therapeutic drug monitoring may be useful in guiding dosage adjustments
and in cases of suspected toxicities. Further research in
this area is needed to elucidate the target serum
concentration of AEDs in neonates in order to
optimize effectiveness and minimize dose-related
adverse effects.

Level II-3 Evidence

A single study reported the pharmacokinetics of
vigabatrin in neonates with uncontrolled seizures.42
Six neonates (15 to 26 days postnatal) were given a
single 125-mg dose of racemic vigabatrin orally.
Blood samples were collected before and at 0.5, 1, 2,
3, 6, 9, 12, and 24 hours after the rst dose. Oral
vigabatrin was then continued at 125 mg twice
daily, for 5 days. Blood samples were drawn prior
to and 1 hour after the morning dose. The
pharmacokinetic model used to describe the data
was not reported.
With respect to the S() enantiomer, the
absorption of vigabatrin (based on a 50 mg/kg
dose) administered orally to neonates was comparable to the values previously obtained in infants
and children.43 The mean Cmax and Tmax were 14
mg/L and 2.1 hours, respectively.42 The AUC or
total drug exposure, however, appeared higher in
neonates (142.6 6 44.0 mg/L/hr), and the elimination half-life appeared longer (7.5 6 2.1 hours).
This can be explained by the reduced renal function
of neonates compared to infants and older children.
On repeated dosing however, no accumulation of
either enantiomer occurred.
Dosage Considerations
The pharmacokinetic prole of vigabatrin (low
plasma protein binding, linear kinetics, eliminated
unchanged in the kidney) along with its wide
therapeutic index make vigabatrin a potentially
desirable agent for use in treating refractory
neonatal seizures. The study by Vauzelle-Kervroedan et al42 demonstrated similar pharmacokinetic
parameters for the active S() enantiomer of
vigabatrin in neonates, as previously reported in
infants and older children,43 suggesting a similar
dosing regimen (vigabatrin, 125 mg orally twice
daily for 5 days) can be used in the neonatal
population. However, further study regarding
42

DISCLOSURE The authors declare no conflicts or

financial interest in any product or service mentioned in
the manuscript, including grants, equipment, medications, employment, gifts, and honoraria.
ABBREVIATIONS AED, antiepileptic drug; AUC, area
under the concentration-time curve
CORRESPONDENCE Joanie Tulloch, PharmD, Childrens and Womens Health Centre of British Columbia,
Department of Pharmacy, 4500 Oak Street, Vancouver,
British Columbia, Canada V6H 3N1 e-mail: joanie.
[email protected]
2012 Pediatric Pharmacy Advocacy Group

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