Journal of Tropical Pediatrics, 2021, 00, 1–9

doi: 10.1093/tropej/fmab041
Original Paper

The Pharmacokinetics of Crushed

Levetiracetam Tablets Administered

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to Neonates
Veshni Pillay-Fuentes Lorente MBChB, PG Dip (Med Dev),1
Adrie Bekker MBChB, MMed (Paed), FCPaed (SA), PhD,2 Gugu T.J.
Kali MBChB, DCH, FCPaed (SA), Cert Neonatol (SA), PhD,2
Lizel G. Lloyd MBChB, DCH, MMed (Paed) FCPaed (SA), Cert
Neonatol (SA),2 Alma W. Van der Merwe BTech,1
Ahmed A. Abulfathi MBBS, MMed (Clin Pharm), FCCP (SA), PhD,1,3
and Eric H. Decloedt MBChB, BSc Hons, FCCP (SA), MMed
(Clin Pharm), PhD1
1
Division of Clinical Pharmacology, Department of Medicine, Faculty of Medicine and Health Sciences, Stellenbosch University,
Cape Town 7505, South Africa
2
Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town 7505,
South Africa
3
Department of Clinical Pharmacology and Therapeutics, Faculty of Basic Clinical Sciences, College of Medical Sciences, University
of Maiduguri, Maiduguri 600004, Nigeria
Correspondence: Veshni Pillay-Fuentes Lorente, Stellenbosch University, Room 7057, Clinical Building, Tygerberg Campus, Francie van Zijl
Drive, Parow, Cape Town 7505, South Africa. Tel: þ27-21-938-9335. Fax: þ27-21-938-9860. E-mail: 14847795@sun.ac.za.

ABSTRACT
Background: Intravenous phenobarbital remains the first-line therapy in the management of neo-
natal seizures. Shortages of intravenous phenobarbital in South Africa necessitated the addition
of oral levetiracetam as part of management of neonatal seizures.
Objective: We evaluated the pharmacokinetics of crushed immediate-release levetiracetam tablets
administered to neonates to terminate seizures.
Methods: A prospective, observational study of neonates admitted with seizures to Tygerberg
Hospital. Participants received crushed levetiracetam (diluted in saline) given orally or via naso-/
orogastric tube. At steady-state, pharmacokinetic sampling was performed at pre-dose, 1.5, 2.5 and 4
h post-dose. Maximum concentration (Cmax), time to Cmax (Tmax), trough concentrations (Ctrough)
and area under the concentration-time curve (AUC0–12) were calculated using non-compartmental
analysis. Seizure termination and safety profiles were documented.
Results: Nineteen participants were grouped into three dosing ranges: (i) 5–15 mg/kg/12-hourly, (ii)
15–25 mg/kg/12-hourly and (iii) 25–35 mg/kg/12-hourly. Range 1 demonstrated AUC0–12
167.0 6 45.6 h*lg/mL, Cmax 19.19 6 4.12 lg/mL and Ctrough 9.99 6 3.86 mg/mL. Range 2, AUC0–12
316.5 6 108.4 h*lg/mL, Cmax 35.12 6 10.54 mg/mL and Ctrough 19.25 6 8.48 mg/mL. Range 3, AUC0–12

C The Author(s) [2021]. Published by Oxford University Press. All rights reserved.
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2  Crushed Levetiracetam Tablets

290.9 (range 176.14–405.59) h*lg/mL, Cmax 36.11 (range 27.58–44.64) mg/mL and Ctrough 13.03
(2.98–23.07) mg/mL. Seizures terminated in 17/19 (90%) neonates by day 3 and 19/19 (100%) by day
4 post-levetiracetam initiation.
Conclusion: Crushed levetiracetam has comparable pharmacokinetics to historical data. No phar-
macokinetic differences were observed between oral vs. naso-/orogastric administration. Crushed
levetiracetam tablets can be considered for neonates in low-resource settings where intravenous and

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syrup access is limited.
LAY SUMMARY

Intravenous preparations of antiepileptic medications are used in the management of neonatal seiz-
ures. Various established standard of care intravenous antiepileptic medicines are unavailable nation-
ally and internationally due to reasons outside our control. This stock shortage included intravenous
phenobarbitone which is the first-line treatment for paediatric seizures. Due to phenobarbital short-
age, levetiracetam has been identified by the neonatologists at Tygerberg Hospital, Cape Town,
South Africa, as a suitable treatment option due to its efficacy and safety profile. However, intraven-
ous levetiracetam and oral syrup is not registered in South Africa. Levetiracetam tablets are being
crushed, dissolved and administered to neonates. There are no data available on the absorption of
crushed levetiracetam tablets administered to neonates via a nasogastric tube. This study character-
ized the pharmacokinetic profile of crushed levetiracetam administered to neonates. We selected
neonates receiving levetiracetam from the neonatal wards at Tygerberg hospital and drew blood to
analyse the levetiracetam concentrations at 4 different time points. We found that the overall expos-
ure of crushed levetiracetam tablets were comparable to the exposures achieved in historical data of
the unaltered formulations. We concluded that crushed levetiracetam tablets can be considered for
neonates in low resource settings where intravenous and syrup access is limited.

K E Y W O R D S : pharmacokinetics, neonatal seizures, crushed levetiracetam

INTRODUCTION seizure control was greater in neonates receiving

The medicine of choice in the management of neonatal
seizures as first-line therapy remains phenobarbital [1,
2]. Neonates are defined as newborns up to 28 days of
life. In February 2018, there was a shortage of intraven-
ous phenobarbital at a national level in South Africa. In
response, the neonatologists at Tygerberg Hospital, a ter-
tiary teaching hospital in Cape Town, South Africa,
opted to incorporate levetiracetam into the neonatal seiz-
ure management algorithm. Oral levetiracetam was intro-
duced as third-line therapy after first-line therapy of oral
phenobarbital in combination with midazolam, followed
by second-line therapy with midazolam, lignocaine or
phenytoin infusion. Immediate-release levetiracetam tab-
lets are registered and marketed in South Africa, but not
the intravenous and syrup formulations. The oral tablets
are cheaper and easily accessible with significantly fewer
cost implications than the intravenous formulation.
Intravenous and oral syrup formulations of
levetiracetam are effective in terminating neonatal
seizures and well-tolerated [3–9]. In a randomized
controlled trial of neonates (n ¼ 100) randomized
to intravenous levetiracetam or phenobarbital,
levetiracetam (RR 0.37; 95% CI 0.17–0.80, p < 0.01)
[10]. No adverse events were reported in the levetir-
acetam arm. In a study evaluating oral levetiracetam
as add-on therapy in paediatric patients who failed
phenobarbital and phenytoin with ongoing seizures,
95.3% of patients responded [11].
Oral levetiracetam is rapidly absorbed, has bioavail-
ability of 100%, linear pharmacokinetics and minimal
hepatic metabolism with no induction or inhibition of
hepatic enzymes [12]. Levetiracetam is a pyrrolidone
derivative thought to exert its pharmacological action
by binding to the synaptic vesicle protein 2A and inhib-
iting presynaptic exocytosis of the synaptic vesicle [13].
Similar levetiracetam pharmacokinetics was demon-
strated in a 3-way crossover study of 10 adult healthy
volunteers, administered levetiracetam with enteral nu-
tritional formulas (ENF) and without ENF [14]. In
children the clearance of levetiracetam is 30% higher
and the exposures are 30–40% lower compared with
adults [12]. Levetiracetam clearance is lower in neo-
nates than children which are attributed to a lower
glomerular filtration rate and plasma esterase activity

[15]. To our knowledge, there are no available data on
crushed levetiracetam in neonates. We sought to gather
more information and assess whether the current
standard practice by the neonatology team of adminis-
tering levetiracetam at a dosing range between 10 and
30 mg/kg/12 h via nasogastric tube, produced adequate
absorption and systemic exposures. In this study, we
evaluated the neonatal pharmacokinetics of crushed lev-
etiracetam tablets 10–30 mg/kg/12-hourly using non-
compartmental analysis (NCA).
METHODS
The study was conducted at Tygerberg Hospital from
August 2018 to July 2019. The study received ethical
approval from the Stellenbosch University Human
Research Ethics Committee and complied with Good
Clinical Practice and the Declaration of Helsinki. We
screened all patients admitted to the neonatal wards
in whom the attending neonatologist prescribed and
initiated levetiracetam. The inclusion criteria were
neonates of all weights and gestational ages receiving
levetiracetam to abort seizures. Signed informed con-
sent by the parent/caregiver was obtained. Neonates
were excluded if they were considered critically ill as
per the discretion of the attending clinician, had a
haemoglobin <7 g/dL and if the pharmacokinetic
sampling blood volumes exceeded the limit of daily
blood draws permitted in neonates as outlined in the
Fig. 1. Timeline representing sequence of study events.
Crushed Levetiracetam Tablets  3
Health Research and Ethics Committee guidelines of
Stellenbosch University [16]. All participants meeting
inclusion criteria received crushed levetiracetam be-
tween 10 and 30 mg/kg/12-hourly either orally or via
a naso- or orogastric tube as per the attending neona-
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tologist’s instructions. The crushing process was uni-
form as per standard of care practice in the neonatal
wards. The 250 mg scored tablet of levetiracetam was
halved and 125 mg (one half) crushed and diluted in
5 ml of saline water, from which the required dose
was extracted. When administered through a naso- or
orogastric tube, 5 ml saline was used to flush the tube
afterwards. The remaining levetiracetam mixture was
discarded. Administration of levetiracetam was
observed by a study team member. The half-life of lev-
etiracetam is between 5 and 7 hours in children [12].
Steady state would have been reached at 5 half-lives
which is 25–35 hours post-initiation of levetirace-
tam. Pharmacokinetic sampling was done at steady
state at 4 time points: pre-dose, 1.5, 2.5 and 4 hours
post-dose, by a medical doctor from the study team
trained to undertake repeated neonatal sampling. Five
minutes variation around the pharmacokinetic sam-
pling time was permissible. The limited time points
were selected to capture the minimum and maximum
concentrations while remaining within blood draw
restrictions. Figure 1 illustrates the sequence of events
in the study. Demographic data such as gestational
4  Crushed Levetiracetam Tablets
age, sex and weight were recorded. Important clinical
findings of the gastrointestinal system were captured,
together with the diagnosis, Apgar scores, daily
Thompson scores and electrolyte abnormalities.
The Apgar score assigns a value of 0, 1 or 2 to heart
rate, reflex irritability, colour, muscle tone and re-
spiratory effort. It is a universally accepted tool
used to assess a neonate at birth. A score of 7 and
above is associated with good health. The
Thompson score is a clinical tool which assesses
central nervous system function in a neonate fol-
lowing hypoxic ischaemic encephalopathy (HIE).
As HIE worsens the Thompson score increases.
Concomitant medication information was recorded
with respect to dose, dosing interval and route of
administration. The timing of medication adminis-
tration was recorded to assess possible drug-to-drug
interactions with levetiracetam. Medical records
were evaluated daily for adverse events possibly
related to levetiracetam by a study member and in-
consultation with the attending clinicians. Adverse
events such as irritability, somnolence and hyper-
activity were evaluated daily. Blood samples
(0.5 mL) were collected in EDTA tubes and centri-
fuged at 4000 rpm within 30 min of blood drawing
to extract plasma. Plasma samples were stored at
80 C until the batched analysis using the ARKTM
levetiracetam assay, a user defined, homogenous en-
zyme immunoassay [17]. The Siemens Dimension
EXL 200 was used to carry out the assay. All sam-
ples were analysed at the Clinical Pharmacology
Laboratory at Stellenbosch University. NCA was
R R
performed using PhoenixV WinNonlinV version 8.1
(Certara USA, Inc., Princeton, NJ, USA).
Maximum plasma concentration (Cmax), time to
Cmax, (Tmax), trough plasma concentration
(Ctrough) and area under the curve from time zero
to 12 h (AUC0–12) were calculated.
AUC0–12 was extrapolated using the pre-dose
concentration as the 12-hour concentration since
participants were dosed 12-hourly. AUC0–12 was cal-
culated using linear up/log down option therefore
AUC0–12 was calculated using linear trapezoidal
method for increasing concentrations and the log
trapezoidal method for decreasing concentrations.
The linear up/log down is a combination of linear
and log trapezoidal method of AUC assessment.
That is, it uses linear interpolation between data
points when levetiracetam concentration is increas-
ing (absorption phase) but logarithmic interpolation
when concentrations are decreasing (elimination
phase). The choice of linear up/log down method
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was to overcome the inherent limitations of using ei-
ther method alone, that is, linear trapezoidal method
overestimates AUC during elimination phase, where-
as the log trapezoidal method underestimates the
AUC during the absorption phase. Therefore, the
linear up/log down method is considered more ac-
curate for AUC assessment.
Descriptive statistics were generated using
R
PhoenixV WinNonlin and GraphPad Prism 8 (San
Diego, CA, USA). Normality testing of the data was
conducted using the Shapiro–Wilk test. Parametric t-
tests were used for normally distributed data and
non-parametric testing for non-normally distributed
data. We used published data evaluating levetirace-
tam pharmacokinetics in 21 children between ages 4
and 12 years old dosed levetiracetam 10–30 mg/kg/
12-hourly as a comparator to our findings [18]. The
means between both data sets were compared using
unpaired T-tests. A p value of <0.05 was used to de-
termine statistical significance between our study
findings and the historical data. The dosing per body
weight range is 10–30 mg/kg/12-hourly and we
grouped participants into three dosing ranges: (i) 5–
15 mg/kg/12-hourly, (ii) 15.01–25 mg/kg/12-hourly
and (iii) 25.01–35 mg/kg/12-hourly.
RESULTS
Twenty-three participants were screened, 4 were
excluded and 19 participated in the study. The rea-
sons for exclusion were withdrawal of levetiracetam
therapy (n ¼ 1), vasculopathy precluding pharmaco-
kinetic sampling by clinicians with relevant expertise
(n ¼ 1) and parents declined participation (n ¼ 2).
Participant characteristics are described in Table 1.
The median 5-min Apgar score was 7 (IQR 6–9). Of
the 15/19 (79%) patients with HIE, 8/15 (53.3%)
were cooled. The highest median Thompson score
and the score at discharge were 11 (IQR 8–16) and
4 (IQR 1.5–5.8), respectively. Five patients (5/19;
26%) received phenobarbitone and levetiracetam; 6/
19 (32%) received midazolam, phenobarbitone, lig-
nocaine and levetiracetam; 4/19 (21%) received
 Crushed Levetiracetam Tablets  5

TABLE 1 Participant characteristics

Characteristics N ¼ 19

Gestational age (weeks), 38 (37–41)

median (IQR)

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Post-natal age (days), 8 (7–13)
median (IQR)a
Preterm, n (%) 5 (26)
Sex, n (%)
Male 9 (47) Fig. 2. Levetiracetam exposures (AUC0–12) in our study
Female 10 (53) compared with a previous study by Fountain, et al. (our
Birth weight (g), 3040 (2840–3310) study;representation of means from Fountain, et al.; pink
median (IQR) dotted lines represent standard deviations from Fountain,
Current weight (g), 3060 (2780–3700) et al.) AUC0–12, area under the curve from 0 to 12 h;
median (IQR)a b.i.d., administered twice a day.
Diagnosis, n (%)
Hypoxic ischaemic 15 (79)
encephalopathy
Meningitis 1 (5)
Otherb 3 (16)
Route of administration, n (%)
Naso- or orogastric tube 14 (74)
Oral 5 (26)
Dose of levetiracetam, n (%)
5–15 (mg/kg/12-hourly) 8 (42)
15–25 (mg/kg/12-hourly) 9 (47) Fig. 3. Concentration–time curves of dosing band 1.
25–35 (mg/kg/12-hourly) 2 (11)

IQR, interquartile range.

a
At the time of pharmacokinetic sampling.
b
Other: diagnosed with congenital abnormalities, choanal stenosis, hya-
line membrane disease and myelomeningocele.

midazolam, phenobarbitone and levetiracetam; 3/19

(16%) received midazolam, phenobarbitone, pheny-
toin and levetiracetam and 1/19 (5%) received
phenobarbitone, lignocaine and levetiracetam. On
discharge, 4/19 (21%) patients received levetirace-
tam and phenobarbitone, 13/19 (68%) were dis-
charged with levetiracetam only and 2/19 (11%)
were not discharged with any anticonvulsant therapy.
Seizures aborted in 21% (4/19) participants by day
1, 58% (11/19) by day 2, 90% (17/19) by day 3 and
100% (19/19) by day 4. No adverse events such as
hyperactivity, somnolence and irritability were
reported.
AUC0–12 in our study was comparable to AUC0–12
described in historical data (Figure 2) [18]. Individual
Fig. 4. Concentration–time curves of dosing band 2.
concentration-time profiles for dosing band 1 and 2
are illustrated in Figures 3 and 4, respectively. Table 2
shows comparison between AUC0–12, Cmax, Ctrough
and Tmax in the current study and historical data.
AUC0–12, Cmax and Tmax were not significantly differ-
ent in participants receiving levetiracetam via naso- or
orogastric tube compared with participants receiving
levetiracetam orally (Table 3).
6  Crushed Levetiracetam Tablets

p valued
DISCUSSION

–
–

–
–
Our study demonstrated that the pharmacokinetics
of crushed levetiracetam tablets administered to neo-
Dose range 3 (25–35 mg/kg/12 h)

290.9 (176.14–405.59)e
nates are similar to the unaltered oral levetiracetam

36.11 (27.58–44.64)e

13.03 (2.98–23.07)e
formulation when dosed between 5 and 25 mg/kg/

1.5 (1.5)e,f
12-hourly. We found similar pharmacokinetics in

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participants receiving levetiracetam either via naso-
or orogastric tube or orally.
Current

There are limited data on the pharmacokinetics

Cmax, maximum plasma concentration; Tmax, time to maximum concentration; AUC0–12, area under the curve from time 0 to 12 h; Ctrough, trough plasma concentration.
data

of crushed oral levetiracetam in children and

neonates. One study evaluated oral levetiracetam in
0.5 (0.5–3)e
73.2 6 19.2

20.6 6 5.8

participants <2 years old administered in a solid or

433 6 94
Historical

crushed form, but included just two neonates and

dataa

only reported trough concentrations [19]. Glauser,

et al. [20] administered a single-dose of 20 mg/kg
b,c

levetiracetam oral solution to infants and children up

TABLE 2 Pharmacokinetic parameters of levetiracetam in our study compared with historical data

0.001
p value

0.88

0.22
–

to 4 years old. In this study [20], levetiracetam

Dose range 2 (15–25 mg/kg/12 h)

AUC0–24 was evaluated, but the differences in the

study design and NCA metrics evaluated makes it
0.5 (0.5–3.0) 2.5 (2.0–3.3)e,f
35.12 6 10.54
316.5 6 108.4

19.25 6 8.48

unsuitable for comparison with our study. We used

Current data

the pre-dose concentration as the 12-hour concentra-

tion to extrapolate AUC0–12 because the levetirace-
tam studies available for comparison to our study
reported AUC from time of dose to 12 hours after
e
57.1 6 14.9

15.6 6 5.3
322 6 71

dose. We did not expect levetiracetam concentra-

Historical

tions at pre-dose to be significantly different from

those at 12 hours post-dose because blood samples
dataa

were collected at steady-state and levetiracetam dosed

12 hourly. We were able to calculate AUC0–12 and
b,c
p value

0.07
0.26

0.34

therefore compared our study findings to a pharmaco-

–

Median (range); all other data expressed as mean (6standard deviation).

Dose range 1 (5–15 mg/kg/12 h)

kinetics study by Fountain, et al. [18]. Fountain, et al.

[18] administered levetiracetam at 10, 20 and 30 mg/
0.5 (0.25–3.0) 1.5 (1.5–2.5)e,f
19.19 6 4.12
167.0 6 45.6

9.99 6 3.86

kg/12-hourly during a titration period of 6 weeks. The

resulting AUC0–12 was similar to our study at corre-
Current

sponding doses. Some patients in our study received

Compared with historical data by Fountain, et al. [18].
data

concomitant phenobarbital which has a cytochrome

Too small sample to compare to historical data.

P450 enzyme inducing effect. However, levetiracetam

e

is predominantly metabolized by enzymatic hydrolysis

24.8 6 8.3
145 6 44

8.4 6 3.8

and is not dependent on the cytochrome P450 system

Historical

for metabolism. Hence levetiracetam concentrations

Compared with historical data.

Non-normally distributed data.

dataa

are unlikely to be affected by phenobarbital or any of

T-test used to assess data.

the other concomitant anti-epileptics administered.

Ctrough (mg/mL)

Patients in the Fountain, et al. study received concomi-

Cmax (mg/mL)

(h*mg /mL)
PK parameters

tant sodium valproate and carbamazepine therapy and

AUC0–12

Tmax (h)

reported similar levetiracetam exposures between the

groups. In dosing range 2, the Cmax in our study was
lower and statistically different from that found in
d
b

e
c

f
a

TABLE 3 Comparison of pharmacokinetic parameters between participants receiving levetiracetam via
naso- or orogastric tube vs. participants receiving the drug orally
Pharmacokinetic parameter Naso- or orogastric tube
administration, n ¼ 14/19
AUC0–12 (h*lg/mL) 220 (157.5–355.4)
Cmax (lg/mL) 23.8 (18.8–41.3)
Tmax (h) 1.5 (1.5–2.5)
All values expressed as medians and interquartile ranges. Maximum plasma concentration (Cmax), time to maximum plasma concentration (Tmax) and
area under the curve 0–12 h (AUC0–12).
a
The study was not powered to specifically compare naso- or orogastric administration vs. oral administration.
Fountain, et al. This could be explained by the dosage
variation within dosing range 2. This was in contrast
with the first dosing range, where majority of the par-
ticipants received 10 mg/kg/12-hourly. The Tmax
values reported in our findings were in keeping with
the Tmax ranges reported by Fountain, et al. and others
[18, 20, 21].
Trough concentrations do not correlate with
efficacy and have high variability [22–24]. Giroux,
et al. [23] found plasma concentrations between 5
and 40 mg/mL with 60% of the responders obtaining
trough concentrations between 6.85 and 40 mg/mL.
Similarly, Sheinberg, et al. [24] reported a Ctrough
range between 2.5 and 38.5 mg/mL. All participants
in our study fell within this range. Chhun, et al. [25]
investigated the appropriate dosing regimen in chil-
dren required to attain the adult target concentration
of 6–20 mg/ml. The probability of attaining the tar-
get trough range of 6–20 mg/mL is 44% when dosed
at 10 mg/kg/12-hourly, 90% at 20 mg/kg/12-hourly
and 66% at 30 mg/kg/12-hourly . This explains why
most of the participants in the current study fell
within the 6–20 mg/mL target range.
The majority of participants had cessation of seiz-
ures by day 3 after levetiracetam initiation which is
in keeping with previous efficacy studies of levetira-
cetam in neonates [26–28]. In a prospective study of
intravenous levetiracetam in 16 neonates as first line
therapy, seizure cessation occurred on average at
96 hours [6]. Another study reported 75% of neo-
nates with seizure cessation by 72 hours after initi-
ation of levetiracetam [29]. In our study, two
participants had abortion of seizures by day 4: one of
the two participants was diagnosed with intracranial
haemorrhage and the other with hypoxia secondary
Crushed Levetiracetam Tablets  7
Oral administration, P valuea
n ¼ 5/19
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213.8 (154.0–348.8) 0.90
26.4 (19.3–34.2) 0.84
2.5 (1.5–2.9) 0.46
to suspected choanal stenosis, possibly contributing
to the seizures. Khan, et al. retrospectively investi-
gated the administration of levetiracetam loading
doses in 22 neonates. Following the loading dose,
32% achieved complete seizure cessation immediate-
ly, 64% by 24 hours, 86% by 48 hours and 100% by
72 hours [4]. The steady state of levetiracetam is
reached within 36–48 hours; this could explain why
79% of our participants achieved seizure cessation
day 2 on levetiracetam as the current practice is
not to give an oral loading dose.
Limitations
Our study had a few limitations. Firstly, due to
restricted blood sampling, we were unable to do a
full pharmacokinetic profile and we had extrapolated
the AUC0–12. Secondly, we lacked a control group.
Furthermore, we did not have other levetiracetam
formulations within our facility to use as a compari-
son. Thirdly, dosing range 3 did not include an ad-
equate representation of participants, therefore we
could not draw conclusions from the participants
receiving levetiracetam doses >25 mg/kg/12-hourly.
Fourthly, our limited sampling strategy that was
largely around the absorption phase did not allow
for a population pharmacokinetic modelling to be
used to reconstruct a full pharmacokinetic profile.
Lastly, adverse events could have been under-
reported, because the most common side effects in
the paediatric population, such as irritability, somno-
lence and hyperactivity as reported previously, are
difficult to assess in neonates [30]. Our study was
not powered to evaluate efficacy of crushed levetira-
cetam tablets in neonatal seizures. Hence, pros-
pective controlled studies should be conducted to
8  Crushed Levetiracetam Tablets
properly evaluate the efficacy of crushed levetirace-
tam tablets in neonatal seizures.
Population pharmacokinetics modelling is the
most suitable approach for analyses of sparse data,
and considering that in the current study we sampled
only during the absorption phase, future studies
should include sparse sampling around the elimination
phase of levetiracetam administered to neonates. This
could then be combined with data from the current
study to enable the reconstruction of a full pharmaco-
kinetic profile of crushed levetiracetam. Therefore,
using a population approach, the pharmacokinetics of
crushed levetiracetam in neonates will be described,
and potential covariates influencing levetiracetam
disposition evaluated. Possible future studies should
also evaluate oral loading doses of levetiracetam.
CONCLUSION
To our knowledge, this is the first neonatal study
evaluating the pharmacokinetics of crushed levetira-
cetam administered to neonates. Crushed levetirace-
tam tablets are soluble and demonstrate comparable
pharmacokinetics to historical data. Seizures were ef-
fectively terminated when using levetiracetam as
add-on therapy. Our study can guide treatment in re-
source-limited settings. We propose that crushed lev-
etiracetam tablets can be administered to neonates in
low resource settings where oral syrup or intraven-
ous levetiracetam are unavailable.
ACKNOWLEDGEMENTS
We would like to acknowledge the Clinical Pharmacology
Laboratory at Stellenbosch University, the staff at Tygerberg
Hospital neonatal wards, the participants and their parents
and caregivers of the participants.
FUNDING
None.
CONFLICT OF INTEREST
None declared.
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