Keywords
antiepileptic drugs - efficacy - epilepsy - perampanel - real-world - tolerability
Introduction
Perampanel (PER) is an orally active, novel, highly selective, noncompetitive α-amino-3-hydroxy-5-methyl-4-isoxazole
propionic acid (AMPA)-receptor antagonist.[1]
[2] PER is approved in the European Union and United States for the adjunctive treatment
of primary generalized and focal seizures in patients with epilepsy aged more than
12 years.
Phase III trials of up to 19 weeks duration have shown Class I evidence that adjunctive
PER is effective in improving seizure control, with acceptable tolerability.[3]
[4]
[5] Furthermore, literature data suggests that the efficacy of PER can be influenced
by the concomitant intake of enzyme-inducing antiepileptic drugs (AEDs) such as carbamazepine
(CBZ), oxcarbazepine (OXC), and phenytoin (PHT).[6]
[7]
The results from regulatory studies are not always predictive of the outcomes in a
real-world clinical setting,[8] mainly because of the patients' selection strict criteria.[9] To date there are only a few number of studies investigating the “real-life” experiences
with PER in drug-resistant focal epilepsies.[10]
[11]
[12]
[13]
[14]
[15]
[16]
[17]
[18] We report the results of an observational study performed at the Epilepsy Unit of
the Spedali Civili di Brescia Hospital (Italy) on the effectiveness and tolerability
of PER as an add-on treatment in adult patients suffering from severe focal epilepsy.
The aim of this study is to assess efficacy and tolerability of PER, used as an add-on
treatment in patients (aged ≥ 12 years) with refractory partial-onset seizures, in
the daily clinical practice setting.
Patients and Methods
We consecutively enrolled all the adult patients who started PER as an adjunctive
treatment at the Epilepsy Unit of the Spedali Civili di Brescia Hospital from May
2015 to February 2016 (“enrolment period”). Patients were followed up for at least
1 year.
All patients suffered from drug-refractory focal epilepsy. Seizure type and seizure
frequency were clinically assessed before the initiation of PER. In all patients,
PER was titrated based on SmPC: treatment was started with 2 mg/day at bedtime, and
was uptitrated by 2 mg/day every 2 to 4 weeks up to a maximum of 12 mg/day. PER was
uptitrated until occurrence of good seizure control or appearance of side-effects.
After initiation of PER, patients were typically seen in consultation every 3 to 4
months. Clinicians and patients usually documented seizure frequency providing a monthly
average since their previous visit. Occurrence of adverse events (AEs) was reported,
as well as withdrawal due to any cause. Clinicians also evaluated reduction in concomitant
antiepileptic drugs (AEDs) and electroencephalography (EEG) improvement. If AEs were
reported, the line of action was different between patients and could result in a
dose reduction or PER withdrawal depending on the severity of AE and efficacy of treatment.
Effectiveness was evaluated comparing seizure frequency between baseline and the mean
frequency in the last 3 months before the last outpatient visit. At every follow-up
visit, an EEG was also performed. The MD was also allowed to reduce doses of other
AEDs due to lack of necessity due to the response to PER. Patients were considered
as “responders” if having a seizure frequency reduction in at least 50%. Aggravation
was defined as any increase in seizure frequency. The same analysis was performed
dividing the cohort in two subgroups of patients taking enzyme-inducing AEDs (CBZ,
OXC, PHT) and non–enzyme-inducing AEDs. In case of discontinuation, the reason was
specified.
Results
Patient Characteristics
The PER was prescribed to 52 patients (M/F = 18/34) during the enrolment period. All
patients were followed up for at least 1 year. Three patients (2 females) were lost
on follow-up; the following analyses were then performed on the remaining 49 patients.
The median age was 38.7 years (range 16–65), and 32 patients (65.3%) were female.
Thirty patients were affected by structural-metabolic epilepsy, while 19 patients
by epilepsy of unknown etiology. Seizure types were focal in 38 patients, and focal
and secondarily generalized in 11 patients. Mean duration of epileptic disease was
28.1 years; in seven (14.3%) patients the onset of epilepsy was within 1 year of age.
The mean number of concomitant AEDs at PER initiation was 2.9.
Three (6.1%) patients had been previously submitted to epilepsy surgery, and three
(6.1%) patients had vagal nerve stimulator. Learning disability was present in 13
(26.5%) patients and psychiatric comorbidity in 7 (14.3%) patients. Mean seizure frequency
at baseline was 13.4/month (range 2–60); 10 (20.4%) patients had daily seizures. Demographic
and clinical details of patients are summarized in [Table 1].
Table 1
Demographic and clinical details of 49 patients
|
Abbreviations: AEDs, antiepileptic drugs; SD, standard deviation.
|
|
Women, n (%)
|
32 (65.3%)
|
|
Mean age, years (SD)
|
38.7 (12.4)
|
|
Duration of epilepsy, years (SD)
|
28.1 (12.6)
|
|
Comorbidities, n (%)
|
|
|
Intellectual and developmental disability
|
13 (26.5%)
|
|
Psychiatric comorbidity
|
7 (14.3%)
|
|
Epilepsy etiology, n (%)
|
|
|
Structural/metabolic
|
30 (61.2%)
|
|
Unknown
|
18 (36.7%)
|
|
Other
|
1 (2.1%)
|
|
Treatment
|
|
|
Surgery, n (%)
|
3 (6.1%)
|
|
Vagus nerve stimulation, n (%)
|
3 (6.1%)
|
|
Number of concomitant AEDs, n (%)
|
|
|
No AEDs
|
0
|
|
1 AED
|
2 (4.1%)
|
|
2 AEDs
|
17 (34.7%)
|
|
3 AEDs
|
18 (36.7%)
|
|
4 AEDs
|
9 (18.4%)
|
|
5 or more
|
3 (6.12%)
|
|
Mean number of concomitant AED
|
2.9
|
|
Number of previous AEDs
|
|
|
Mean (SD)
|
7.7 (3.2)
|
|
Range
|
2–18
|
|
Hepatic enzyme inducers, n (%)
|
31 (63.3%)
|
Efficacy
After 12 months since PER initiation, mean PER dosage was 7.57 mg/day (standard deviation,
SD 2.5, range 4–12 mg/day). The responder rate was 57.14% (28 patients); five (10.2%)
patients were seizure free. In addition, six (12.2%) patients reported a seizure reduction
of less than 50% (see [Table 2]). Four (8.16%) patients had an improvement in their EEG, and eleven (22.4%) patients
reduced the dosage of at least one concomitant AED. Seizure worsening was reported
in five (10.2%) patients.
Table 2
Effect on seizure frequency after 1 year of treatment with PER
|
Nonresponders
|
n
|
%
|
|
Abbreviation: PER, perampanel.
|
|
Worsened
|
5
|
10.2
|
|
Unchanged
|
10
|
20.4
|
|
Reduction < 50%
|
6
|
12.2
|
|
Total
|
21
|
43
|
|
Responders:
|
n
|
%
|
|
Reduction > 50%
|
23
|
46.9
|
|
Seizure free
|
5
|
10.2
|
|
Total
|
28
|
57
|
Compared with the whole set of patients, the subgroup that reached seizure freedom
had a later mean age-of-onset of disease (17.6 vs. 9.9 years), a shorter duration
of epilepsy (21.6 vs. 28.6 years), and a lower monthly seizure frequency at baseline
(2.8 vs. 14.6). Three patients achieved seizure freedom in the first 3 months after
PER initiation, while the other two attained the same result after 6 and 9 months,
respectively. They became seizure free with a mean dosage of 6.4 mg of PER after 1
year of treatment.
When subdividing the patients based on the etiology, we found that the responder rate
in patients affected by epilepsy of unknown etiology was higher than in structural-metabolic
epilepsy, respectively, 68.4 versus 50.0%.
Adverse Effects
Twenty-one (42.9%) patients reported at least one AE. The most frequent were sedation
in 11 (22.4%) patients, dizziness/ataxia in 6 (12.2%) patients, behavioral changes
(mainly aggressivity) in 5 (10.2%) patients, and headache in 3 (6.1%) patients. Other
complaints were gastrointestinal disturbances, weight gain, transient blurred vision,
and falls ([Table 3]). Three out of five (60%) patients that developed aggressive behavior had a history
of learning disability, compared with 10 out of 44 patients (22%) who did not display
this adverse effect.
Table 3
Summary of adverse events
|
n
|
%
|
|
Sedation
|
11
|
22.45
|
|
Dizziness/ataxia
|
6
|
12.25
|
|
Aggressivity
|
5
|
10.2
|
|
Headache
|
3
|
6.12
|
|
Nausea
|
2
|
4.08
|
|
Blurred vision
|
1
|
2.04
|
|
Falls
|
1
|
2.04
|
|
Weight gain
|
1
|
2.04
|
Sixteen (32.65%) patients withdrew PER, after a mean duration of treatment of 163.1
days (SD = 100.2, range 28–336 days). In four (8.2%) patients, this was due to lack
of efficacy, while in 5 (10.2%) patients, the reason for discontinuation was the presence
of intolerable AEs. Mean dosage of PER in this subgroup of patients was 6.4 mg (range:
4–12).
When comparing the patient who did develop any AE with the ones who did not, we found
that the former was taking a lower dose of PER (6.6 mg vs. 7.5 mg), had a higher seizure
frequency at baseline (15.9 vs. 11.5), and were taking the same number of comedication
at baseline (2.95 vs. 2.82).
Comedication with Hepatic Enzyme-Inducing Antiepileptic Drugs
Thirty-one patients (63.3%) were also taking hepatic enzyme-inducing AEDs (CBZ, OXC,
and PHT). In this subgroup of patients, efficacy was lower than in patients not taking
hepatic enzyme-inducing AEDs. These patients also displayed a higher frequency of
AEs and a higher rate of withdrawal from medication. The data are summarized in [Table 4].
Table 4
Efficacy and side-effects in patients with and without enzyme–inducing AEDs
|
Patients with enzymatic inducer (n = 31)
|
Patients without enzymatic inducer (n = 18)
|
OR
|
p–Value*
|
|
Abbreviations: AEDs, antiepileptic drugs; OR, odds ratio.
*Two–tailed Fisher's exact test.
|
|
Seizure freedom, n (%)
|
1 (3.2%)
|
4 (22.2%)
|
0.11
|
0.05
|
|
>50% seizure reduction, n (%)
|
14 (45.2%)
|
14 (77.7%)
|
0.23
|
0.03
|
|
Worsened seizure frequency, n (%)
|
5 (16.1%)
|
0 (0%)
|
0.43
|
0.14
|
|
Side-effects, n (%)
|
15 (48.4%)
|
6 (33.3%)
|
1.87
|
0.37
|
|
Withdrawal of medication, n (%)
|
13 (41.9%)
|
3 (16.6%)
|
3.61
|
0.11
|
Discussion
The efficacy, safety, and effectiveness of PER as an add-on treatment in patients
with focal and generalized seizures have been demonstrated in controlled trials. The
effects of PER in the everyday clinical practice are still being studied, especially
regarding the side-effects profile and the possible factors leading to a better response
to treatment.
In our cohort of adult patients with focal refractory epilepsy treated with PER for
1 year, we observed a responder rate of 57.14%, including 10.2% seizure-free patients.
These results are consistent with the outcomes reported in the regulatory studies,[10]
[11] and show a better efficacy compared with some of the real-world studies.[12]
[19]
One possibility for the differences between these studies could be a diverse epilepsy
severity between groups. Nevertheless, our cohort of patients represents a highly
refractory sample, as can be seen by a high number of concomitant AEDs, long story
of epilepsy, and large proportion of patients with learning disability or psychiatric
comorbidity. One other possibility that can explain this difference may lie in the
higher mean PER dosage (7.57 mg/day) of our sample compared with those reported in
previous investigations (5.8 mg/day[9]), and more similar to the regulatory studies (8.8 mg/day[10] and 7.7 mg/day[11]). Therefore, we can suggest that in clinical practice, when treating patients with
an incomplete response to low PER dosage, it might be appropriate to proceed to further
increase in PER dosage to achieve clinical improvements. Caution about potential increase
in side-effects, that are also dose dependent, must be used. Furthermore, the characteristics
of the seizure-free patients in our cohort suggest that patients with a shorter duration
of disease and an overall less severe disease at baseline may achieve better results
even with lower dosages.
We also found a better response to treatment in patients with epilepsy of unknown
etiology when compared with structural-metabolic etiology. This finding is interesting
and could help shed some light on the baseline characteristics of patients who would
most benefit from treatment with PER.
Talking about side-effects, we found that 42.9% of patients experienced AEs, which
is lower than what reported in pooled analysis of the phase III studies (77% in Steinhoff
et al[20]) as well as in other clinical samples (52.0% in Steinhoff et al,[11] 67.4% in Shah et al[21]). This is of relevance, considering the prospective nature of the study and the
mean dosage of PER used in our sample. The most commonly reported AEs were dizziness
and somnolence, similar to those reported in the core randomized controlled trials
(RCTs) of PER and the real-world studies.[10]
[11] Also, the most frequently reported psychiatric AE was aggressivity (8.16%), mirroring
the results of previous studies,[10]
[11]
[12] while another study reported a higher frequency of behavior/mood disturbances (18.1%[19]). One reason for these discrepancies may lie in the different methods for evaluating
psychiatric disturbances: in fact, we did not use specific assessment scales for psychiatric
disorders, and this could have led to an underestimation of these AEs. Also, different
baseline patients' characteristics could explain this variability. In our cohort,
we found a higher seizure frequency at baseline in those reporting AE, but a lower
dosage of PER. This may be explained by the fact that, in those not displaying side-effects,
it was possible to reach higher dosages. On the other hand, a higher seizure frequency
at baseline could be an independent risk factor; further studies with higher number
of patients are needed to address this issue.
Alongside demonstrating real-world safety and efficacy, we also attempted to clarify
whether the comedication with hepatic enzyme-inducing AEDs was associated with inferior
clinical responses or augmented risk of AEs. Patients using concomitant enzyme-inducing
AEDs had lower clinical responses to PER, with a responder rate of 45.2% (versus 77.7%
in the subgroup without enzyme-inducing AEDs), along with a higher frequency of AE.
This has also been reported in RCT and observational studies.[6] These results support the hypothesis that PER concentrations are lower in patients
with enzyme-inducing AEDs than in those without,[7] causing a lower clinical effect.[13] Subsequently, clinicians should consider an increase in the dose of PER when combining
it with a hepatic inducer. Nevertheless, the high frequency of AEs in this subgroup
suggests that adverse effects are not dependent on the PER concentrations.
Our study has some limitations. We included a cohort of patients with refractory epilepsy
of various types and etiology. No specific psychiatric assessments were performed
at baseline to detect behavioral and psychiatric comorbidity, and data about the blood
concentrations of PER were not available. Alongside, the long duration and prospective
nature of this work in a “real-life” setting provide reliable real-world data, offer
the potential for a fuller dataset, and can offer information on longer-term safety.[9]
[14]
[15]
[22]
Conclusion
Adjunctive therapy with PER for treating focal seizures in refractory patients can
achieve clinically meaningful improvement in a high percentage of patients. Furthermore,
this treatment was generally well tolerated. Comedication with enzyme-inducing AED
can limit the efficacy and tolerability of PER treatment.
