Epileptic Disorders
MENUPreliminary efficacy of levetiracetam in children Volume 5, supplément 1, Supplement, May 2003
Illustrations
Auteur(s) : Tracy A. Glauser1, Olivier Dulac2
1 Cincinnati Children’s Hospital Medical Center,
Cincinnati, Ohio, USA
2 Hôpital Saint Vincent de Paul, Paris, France
Introduction
Although existing antiepileptic drugs (AEDs) provide effective
seizure control in a majority of children, more than 25% of
pediatric patients treated with these AEDs experience
treatment-resistant seizures or intolerable adverse events [1]. The
clinical consequences of intractable or poorly controlled epilepsy
can be significant; for example, growth and cognitive development
may become impaired [2].
Selecting appropriate AED therapy for pediatric patients may not
be easy, however. Few well-controlled studies have been carried out
to determine AED efficacy in the treatment of childhood epilepsy.
Children are often excluded from clinical trials of antiepileptic
medications prior to approval, and historically, there has been
little incentive to conduct trials in this patient population once
a drug has been approved. There also exist methodological problems
related to variable response according to various types of epilepsy
[3, 4]. However, conclusions about efficacy and safety based on
clinical trials in adults may not always be translatable to
pediatric patients.
There are numerous differences between pediatric and adult
epilepsy; for example, age-related seizure types, etiologic
differences in partial seizures between adults and children, and a
higher frequency of special age-related epilepsy syndromes [5-7].
Moreover, children with partial epilepsy tend to have frequent
comorbidities, including mental retardation and behavioral
problems, that may affect the selection of AEDs due to concerns
over potential side effects.
While safety data regarding dose-dependent or titration-related
side effects (eg, sedation, cognitive impairment, rash, headache,
nausea) in adults with partial seizures are translatable to
children, unpredictable/idiosyncratic side effects (eg, hepatic
failure, aplastic anemia), reactions to long-term therapy (eg,
tolerance/dependence, weight gain/loss), and delayed effects (eg,
teratogenicity, carcinogenicity) are not. In children, neurotoxic
side effects may be more subtle, and dermatologic reactions more
common, possibly because usual comedication is different [7]. Drugs
that typically sedate adults may have the opposite effect—increased
irritability and hyperactivity [7].
Significant changes in AED pharmacokinetics occur from birth to
adolescence [7]. Some pharmacokinetic parameters (eg, percent
metabolized, effect on cytochrome P450 enzymes/potential for
drug-drug interactions) may be consistent across patient
populations, but others may vary. Age affects half-life, time to
steady state, bioavailability, and drug elimination.
Thus, when bringing to the market a new compound for children,
several sets of data in addition to those drawn from studies in
adults are required. Tolerability may be different, including
between infants and children. Pharmacokinetics is clearly distinct
across age ranges, with major differences between newborns,
infants, and children. Efficacy according to seizure types needs to
be studied because there are age-specific seizures. However,
age-related syndromes are also specific in terms of response to
drugs, both for benefit and risk of worsening.
Levetiracetam, a novel AED structurally unrelated to other AEDs,
has been shown to be effective as adjunctive treatment in adults
with partial seizures with or without secondary generalization, and
well tolerated [8]. This paper reviews findings to date on
levetiracetam in children.
Clinical experience
Refractory partial seizures
An open-label study of children with treatment-resistant
partial-onset seizures with or without secondary generalization
provided preliminary information on the efficacy and safety of
levetiracetam in children [9]. Levetiracetam (target dose
40 mg/kg/day) was administered as add-on therapy to one other
AED (carbamazepine, felbamate, gabapentin, lamotrigine, primidone,
topiramate, or valproic acid) in 24 patients between
6 and 12 years of age. A 4-week baseline period was
followed by a 6-week dose-titration phase and an 8-week evaluation
phase. Efficacy data were evaluable in 23 patients, and
22 completed the study. Twelve (52.2%) of the evaluable
patients experienced a 50% or greater reduction in seizure
frequency during the evaluation phase, and two patients remained
seizure-free during this period. The median percentage reduction in
partial-onset seizures was 53% (N = 23), with a
mean group reduction of 29.8% from baseline. The median and mean
group percentage reductions by seizure type were simple partial
seizures 26.4% and 22.1% (N = 7), respectively;
complex partial seizures 46.9% and 13.5% (N = 19),
respectively; and partial secondarily generalized seizures 64% and
45.9% (N = 8), respectively.
Adding levetiracetam to the therapeutic regimen did not affect the
plasma concentrations of co-administered AEDs. The safety profile
of levetiracetam in this small cohort of children was very similar
to that in adults [10]. The most commonly reported adverse events
were headache, infection, anorexia, and somnolence. The effect on
weight was neutral: three patients experienced significant weight
gain, while two experienced significant weight loss.
Lennox-Gastaut syndrome and related conditions
Lennox-Gastaut syndrome is characterized by multiple types of intractable seizures, including mainly tonic and atonic seizures. It is one of the most difficult epilepsy syndromes to treat and can have a devastating impact on a child’s development [11]. Nosological limits remain, making it often difficult to determine, in clinical practice, the distinction between Lennox-Gastaut syndrome and its so-called myoclonic variant, which is probably related to myoclonic astatic epilepsy [12,13]. De los Reyes and associates identified six patients 2.5 to 16 years of age who received levetiracetam as add-on therapy for the management of these conditions [14]. An initial dose of 10 mg/kg/day was adjusted weekly depending on the patient’s clinical response. Patients were followed for 1 to 11 months (mean, 5.6 months). All were taking a minimum of two medications, and one patient was receiving four. A 100% reduction in seizure frequency was observed in four patients with myoclonic seizures and in three of four patients with generalized tonic-clonic seizures. A reduction of ≥ 50% was observed in patients with atonic (N = 2), generalized tonic-clonic (N = 1), and tonic (N = 1) seizures. The most common side effects were somnolence and irritability, which caused levetiracetam to be discontinued in one patient.
Generalized seizures
Most children with epilepsy have partial or generalized seizures, hence the importance of evaluating AEDs in pediatric patients with these conditions [15, 16]. Adjunct levetiracetam therapy was evaluated retrospectively by Barron et al. in 18 children with multiple types of generalized seizures (average age, 10.3 years) [17]. Patients were already taking valproate, lamotrigine, topiramate, and/or zonisamide. The average dose of levetiracetam was 29 mg/kg/day (range, 15 to 52 mg/kg/day). Ten patients had at least a 50% decrease in seizure frequency after the addition of levetiracetam and six experienced a ≥ 75% reduction. Three patients became seizure-free. Six patients experienced adverse events (decreased appetite, asthenia, and behavioral changes); however, these side effects did not lead to the discontinuation of levetiracetam.
Various seizure types
Several recent small-scale studies have looked at the efficacy
and tolerability of levetiracetam in pediatric patients. These
patients represent a wide range of seizure types.
Bourgeois et al. assessed the safety and efficacy of
levetiracetam as add-on therapy in 65 patients (mean age,
12.8 years; range, 2 to 34 years, with only nine of
the 65 patients older than 18 years of age) with various
seizure disorders (54% localization-related, 46% generalized) [18].
This group of patients had treatment-resistant seizures; the mean
number of previously tried AEDs was 7.6, and 23.1% had undergone
epilepsy surgery. Patients received a mean levetiracetam dose of
35 mg/kg/day and were followed for an average of
5.6 months. Levetiracetam was effective (based on responder
rate of 50% or greater decrease in seizure frequency) against
focal-onset as well as primarily generalized seizures (figure 1). Four patients
became seizure-free. Fifteen patients discontinued treatment
because of lack of efficacy, eight because of adverse effects.
Adverse events occurred in 16 patients, with behavioral
problems most common (10/65, 15% of patients).
Mandelbaum et al. treated 26 pediatric patients
(median age, 5.3 years) with levetiracetam (mean,
43.6 mg/kg/day) for uncontrolled epilepsy [19]. At the end of
3 months, 24 were still taking levetiracetam. Of these,
12 experienced a ≥ 50% decrease in seizure frequency
and six were seizure-free. Three were receiving levetiracetam
monotherapy. None of the patients discontinued due to adverse
events. The adverse events noted most often in this cohort were
mood swings and lethargy.
Ng and Wheless administered levetiracetam as add-on therapy for
partial or generalized refractory seizures in a prospective study
that included 39 children (mean age, 8.6 years),
28 of whom had developmental delay or mental retardation [20].
Patients received an average maintenance dose of
53.3 mg/kg/day and were followed for an average of
5.9 months. Four (7.7%) of the 39 patients became
seizure-free, while eight (15.4%) had > 90% reduction in
seizure frequency and six (11.5%) had a 50% reduction in seizure
frequency. Eight patients discontinued due to either lack of
efficacy or adverse events. The most common adverse events were
behavioral (i.e., hyperactivity, agitation, positive psychotropic
effects, or sedation).
The records of 50 children (median age, 6 years) were
reviewed by Gustafson et al. [21]. Patients received
levetiracetam (mean dose, 46 mg/kg/day) as add-on therapy for
a variety of seizure disorders and were followed for at least
6 months. All had refractory seizures and had failed to
respond to previous therapy (mean, seven AEDs). Eight patients
became seizure-free after the addition of levetiracetam, and four
were converted to levetiracetam monotherapy. An additional six
children had a ≥ 50% decrease in seizure frequency.
Improvements were seen in partial-onset seizures, atypical absence,
tonic, tonic-clonic, and myoclonic seizures. Ten children
discontinued levetiracetam because of adverse events. Nine stopped
therapy because of behavioral disturbances; however, six of these
had a history of such problems.
Hovinga and colleagues reviewed the records of 27 pediatric
patients (median age, 12 years) with various seizure disorders
who had levetiracetam (median dose, 35 mg/kg/day) added to
their antiepileptic therapy [22]. After the addition of
levetiracetam, the median seizure frequency decreased from
12.5 to 7.0 seizures/week, and 22% of patients became
seizure-free. Focal seizures decreased by 87%. Physicians were able
to reduce the dose of or discontinue the concomitant AED in 52% of
patients, and four were converted to monotherapy. Adverse events
occurred in 52% of patients and led to the discontinuation of
levetiracetam in 11%. Adverse events tended to be CNS-related.
In another retrospective study, Strunc and Levisohn reviewed the
records of 19 children (mean age, 10 years) with either
idiopathic generalized epilepsy or symptomatic localization-related
epilepsy who had levetiracetam added to their therapy [23]. Five
patients (26%) had a > 50% reduction in seizure
frequency, and an additional four patients (21%) became
seizure-free. Behavioral and cognitive side effects led to a
decrease in the dosage of levetiracetam in two patients and to the
discontinuation of levetiracetam in two other patients. Improved
behavior was reported in one patient.
Faircloth et al. focused on refractory focal-onset seizures
with or without generalization [24]. Their retrospective review
included 27 children (mean age, 9.9 years) who received
levetiracetam (mean dose, 32 mg/kg/day) as add-on therapy and
were followed for a mean of 6 months. Two children
discontinued treatment within 1 month because of side effects.
A 50% or greater reduction in seizure frequency was reported in 16
(64%) of the 25 children who continued treatment, while 13
(52%) had a > 75% decrease and seven (28%) became
seizure-free. Twelve (44%) children experienced adverse events,
which were generally mild. Behavioral/psychiatric symptoms were
most common and were reported in six patients; three of these
patients had pre-existing behavioral disorders. Four patients
discontinued treatment because of behavioral side effects.
Prospective tolerability study
To assess the tolerability of levetiracetam, Wannag and colleagues prospectively evaluated 45 children (mean age, 10 years) whose epilepsy was treatment-resistant despite having tried an average of nine AEDs [25]. Approximately half of the patients achieved significant seizure reduction (50% or greater) on levetiracetam doses of 10 to 20 mg/kg/day. Over 3 to 5 months of follow-up, adverse events (ataxia, dizziness, lethargy, and ’forced normalization’) were reported in four patients. At the end of the observation period, 27 (60%) remained on levetiracetam therapy. Doses > 30 mg/kg/day were less effective than doses < 30 mg/kg/day and were associated with increased seizure frequency.
Psychosis in children
Recently, Kossof et al. reported the development of acute psychosis in four patients aged 5 to 17 years [26]. Symptoms occurred within 2 days to 3 months of the initiation of levetiracetam therapy and resolved rapidly when levetiracetam was discontinued. All four patients had cognitive deficits, and the three adolescents had mild behavioral abnormalities prior to receiving levetiracetam.
Dosing guidelines
The pharmacokinetics for any given drug are likely to be more
variable and less predictable in children than in adults. When
treating pediatric epilepsy patients, drug dosing is complicated by
age-related changes in drug metabolism and pharmacokinetics and the
need to minimize interference with normal development.
Pellock and associates evaluated the pharmacokinetics of
levetiracetam in 24 children (mean age,
9.4 ± 2.2 years; range, 6 to 12 years of
age) with partial seizures in a multicenter, open-label,
single-dose (20 mg/kg) study [27]. Their findings are shown in
table 1.
Table 1. Pharmacokinetics of levetiracetam after a single dose of 20 mg/kg [27]
Parameter | Mean ± SD (n = 24) |
---|---|
Dose (mg/kg) | 19.6 ± 4.6 |
CLCR (mL/min/1.73 m2) | 80.6 ± 27.2 |
Cmax (μg/mL) | 25.8 ± 8.6 |
Tmax (h) | 2.3 ± 1.2 |
AUC (μg/h/mL) | 241 ± 76 |
λz (h – 1) | 0.120 ± 0.022 |
t1/2 (h) | 6.0 ± 1.1 |
CL/f | |
(mL/min/kg) | 1.43 ± 0.36 |
(mL/min/1.73 m2) | 72.7 ± 18.1 |
Fe (0-24h) (%) | 51.9 ± 13.8 |
CLRR | |
(mL/min/kg) | 0.79 ± 0.26 |
(mL/min/1.73 m2) | 39.5 ± 12.8 |
CLNR | |
(mL/min/kg) | 0.64 ± 0.32 |
(mL/min/1.73 m2) | 32.3 ± 16.5 |
VZ/f (L/kg) | 0.72 ± 0.12 |
CLCR, creatinine clearance; Cmax, maximal plasma concentration; tmax, time to reach maximal concentration; AUC, area under the plasma concentration-time curve extrapolated to infinite; λz, elimination rate constant; t1/2, half-life; CL/f, apparent total body clearance; Fe(0-24 h), 24-h cumulative urinary excretion; CLR, renal clearance, CLNR, non-renal clearance; VZ/f, volume of distribution.
The maximum plasma concentration and area under the curve,
equated for a 1mg/kg dose (1.33 μg/mL and 12.4 μg/h/mL,
respectively) is comparable to that reported for adults
(1.38 μg/mL and 11.5 μg/h/mL, respectively) [28, 29].
Apparent total body clearance of levetiracetam in children was
approximately 30% to 40% higher than in adults. The variability in
the elimination half-life (4.0 to 8.2 hours) could not be
explained by interpatient differences in age or creatinine
clearance.
These findings suggest that pediatric patients may require a daily
maintenance dose equivalent to 130% to 140% of the usual adult
daily maintenance dose (1000 to 3000 mg/day). However, it
is likely that the increase, compared with adults, is even higher
in infants, for whom the data remain insufficient. As when
administering any AED, a key principle is to ’start low and go
slow’ (table 2).
Table 2. Dosing suggested for levetiracetam in pediatric patients*
• Initial dose: 10 mg/kg/day |
• Titration rate: increase by 10 to 20 mg/kg/week |
Discussion
When prescribing AED therapy for pediatric patients, the
clinician must carefully balance both drug efficacy and safety.
While adverse events in pediatric patients are similar to those
that occur in adults, the incidence may differ, and normal
development is a concern over the long term. Some AED-related
adverse events are particular to children and may not be predicted
on the basis of safety data obtained from adults. For example, the
risk of a severe dermatologic reaction to lamotrigine is
significantly higher in children than in adults [4].
Neurobehavioral changes have been observed with virtually all
agents [29] and are a particular concern for the developing child
[4]. Levetiracetam is generally well tolerated in pediatric
patients. Adverse behavioral or psychological reactions may occur
but appear to resolve quickly when treatment is discontinued. The
full side effect profile of levetiracetam is still being
determined.
Several ongoing studies of levetiracetam will provide further
information on the pharmacokinetics, efficacy, and tolerability of
levetiracetam in pediatric patients. A multiple-dose study in
children 4 to 12 years of age with treatment-resistant
partial-onset seizures will further study pharmacokinetics,
including potential drug-drug interactions. Efficacy and safety
will be assessed in a large randomized, double-blind,
placebo-controlled multicenter trial of patients 4 to
16 years of age with uncontrolled partial-onset seizures and
on a stable AED regimen.
Both children and adults will participate in another large
randomized, double-blind, placebo-controlled multicenter study. The
study population will include patients experiencing idiopathic
generalized epilepsy with primary generalized tonic-clonic seizures
that are uncontrolled despite treatment with other AEDs.
These new data should be very helpful. However, some additional
pharmacokinetic data in infants and young children will be
required. As with all newly marketed AEDs, physicians will need to
be vigilent to identify idiosyncratic age-related side effects, and
determine whether some types of epilepsy worsen.
Conclusions
The goal of AED therapy is to produce the best quality of life with complete control of seizures without causing untoward side effects. Results from small prospective and retrospective studies provide strong support for the efficacy and safety of levetiracetam in pediatric patients with a wide range of seizure disorders. Data from these and other studies will help determine whether levetiracetam can be considered as a first-line treatment option or monotherapy in children with epilepsy. In the absence of sufficient data, certain criteria can help assess suitability as first-line therapy: effectiveness in two or more randomized, double-blind controlled trials, a favorable safety profile, no idiosyncratic adverse reactions, and ease of use [30]. In the meantime, clinical findings suggest that levetiracetam could be an effective and well-tolerated treatment option in children with refractory epilepsy. The need exists for additional pediatric clinical data regarding levetiracetam’s efficacy, pharmacokinetics, and tolerability.