Epilepsy is common in older adults; Causes of new-onset epilepsy in older ages include cerebrovascular disease, dementia, Alzheimer’s, brain tumor, neurodegenerative disorders, and traumatic head injury. The incidence of treated epilepsy is estimated at 80.8 per 100,000 in the general population, rising to 85.9 per 100,000 in those aged 65 to 69 years, and 135.4 per 100,000 in those aged ≥ 85 years.
Mortality rates for people with epilepsy are 3.1, 1.7, and 2.0 times higher than those of the general population for those aged 60–69, 70–79, and ≥80 years. The effects of age on the pharmacokinetics (PK) and pharmacodynamics of antiepileptic drugs (AEDs) mean that AED selection and dosing may need adjustment in this population. These patients often receive concomitant medications for multiple comorbidities. Therefore, enzyme induction by some AEDs poses a challenge for optimal polypharmacy in older patients.
There are relatively few randomized controlled trials (RCTs) of AEDs in older populations. Current evidence supports the use of lamotrigine or levetiracetam (LEV) as first-line AEDs in older patients with epilepsy. Brivaracetam (BRV), a selective, high-affinity synaptic vesicle protein 2A ligand, has been approved by the US, Canada and Europe as an adjuvant treatment for focal seizures in adults (≥16 years) with epilepsy, with good tolerance . The objective of the present analysis was to evaluate the tolerability, safety and efficacy of BRV for the adjuvant treatment of focal seizures in older patients, using a post-hoc analysis of pooled data from three studies that included patients aged 65 years or older.
| Results |
> Patient disposition . 1558 patients were randomized, of whom 38 were ≥65 years old. Of these, 32 were randomized to receive placebo (n = 8) or BRV 50–200 mg/day (n = 24). In total, 30/32 patients (93.8%) completed their respective studies; 2/32 (6.3%) discontinued it due to adverse effects.
> Demographic data and baseline characteristics. At baseline, patients ≥ 65 years of age had a mean (standard deviation, [SD]) age of 72.1 (4.2) years vs. 69.3 (3.6) years, and 57.1% and 54.2% were men, in the placebo and BRV groups, respectively. Patients had long-lasting epilepsy (mean [SD] duration: 24.8 [14.7] vs. 34.1 [20.6] years), and a median focal seizure frequency/28 days at baseline of 9 .6 vs. 7.5, for the placebo and BRV groups, respectively. Most patients had previously discontinued ≥2 AEDs; more than half had previously discontinued LEV. The most common concomitant AEDs were oxcarbazepine, carbamazepine, lamotrigine, and lacosamide.
> Safety and tolerability. In patients ≥65 years (n = 32), the mean (SD) drug exposure was 81.1 (12) days for placebo and 82.6 (18) days for BRV. In total, 7/8 (87.5%) placebo patients vs. 16/24 (66.7%) with BRV reported treatment-emergent adverse events (TEAEs) during the treatment period. Of these, 5/8 (62%) with placebo vs. 13/24 (54.2%) with BRV reported drug-related TEAEs.
Few patients discontinued study drug due to TEAEs: 1/8 (12.5%) placebo patients and 1/24 (4.2%) BRV 100 mg/day patients. The most frequently reported TEAEs were headache (placebo 2/8; 25% vs. BRV 3/24; 12.5%), paresthesias (0/8; 0% vs. 3/24; 12.5%), and somnolence (4/8; 50.0% vs 3/24; 12.5%). There were no serious TEAEs in the placebo group, and in the BRV group one woman suffered trauma after a seizure, so the drug was permanently discontinued.
After completion of the core study, serious adverse events were observed in one patient in the placebo group (who resolved) and in two treated with BRV. The latter two died of sepsis, so it was not considered likely that both deaths were related to the study drug.
The number of patients was small; however, there were no trends of clinical concern in laboratory evaluations
> Efficiency. In patients ≥65 years (n = 31), the median percentage reduction from baseline in focal seizure frequency/28 days was 14% (placebo) vs. 25.5%, 49.6% and 74.9% (BRV 50, 100 and 200 mg/day, respectively). Similarly, the ≥50% response rate was 1/7 (14.3%) for placebo vs. 1/4 (25%), 7/14 (50%) and 4/6 (66.7%) for BRV 50, 100 and 200 mg/day, respectively. Efficacy appeared to increase with increasing BRV dose, although the number of patients was small. The number of patients continuously seizure-free (all types) was 0/7 (placebo) vs. 3/24 (1/4, 1/14 and 1/6 patients for BRV 50, 100 and 200 mg/day, respectively).
| Discussion and conclusions |
In this small subgroup of patients treated with adjuvant BRV, comprehensive evaluation of TEAEs and laboratory evaluations did not reveal any problems of clinical interest. Seizure control rates were higher with BRV than with placebo and compared favorably with those seen in the pooled general population. In fact, seizure reduction rates were higher than for the general population. Of note, the population analyzed here had long-standing epilepsy and the majority had received ≥2 prior AEDs; therefore, it was not typical for patients with new-onset epilepsy at older ages.
BRV has several characteristics that make it a potential favorable option for older patients, although with caution in this population; A lower dose may be necessary in patients with decreased hepatic, renal, or cardiac function. BRV has a low potential to induce or inhibit the cytochrome system, except for CYP2C19 which is involved in the secondary metabolism of BRV. It acts as a moderate inhibitor of epoxide hydrolase. In pivotal trials, BRV showed a favorable safety and tolerability profile and no titration was required for tolerability reasons.
Limitations of this analysis include its post-hoc nature and the small number of patients ≥65 years of age. A higher age limit or more age stratifications could be useful in future studies, as well as studies in patients with late-onset epilepsy.
Based on these results, BRV may be a suitable adjunctive treatment for older patients with uncontrolled focal seizures. However, due to the small number of patients in this analysis, additional studies in this population should be warranted.
