Mechanism of Action
Perampanel is a non-competitive antagonist of the ionotropic α-amino-3-hydroxy-5-methyl-4isoxazolepropionic acid (AMPA) glutamate receptor on post-synaptic neurons. Glutamate is the primary excitatory neurotransmitter in the central nervous system and is implicated in a number of neurological disorders caused by neuronal over excitation.
The precise mechanism by which FYCOMPA exerts its antiepileptic effects in humans has not been fully elucidated.
In a healthy volunteer study to assess the effects of FYCOMPA on psychomotor performance using a standard battery of assessments including simulated driving, single and multiple daily doses of FYCOMPA 4 mg did not impair simple psychomotor tasks, driving performance or sensori-motor coordination. Single and multiple doses of 8 mg and 12 mg impaired psychomotor performance in a dose-related manner. Car handling ability was impaired after dosing of FYCOMPA 12 mg, but postural stability was not significantly impaired. Performance testing returned to baseline within 2 weeks of cessation of FYCOMPA dosing.
Interactions with Alcohol
In the above study (See Psychomotor Performance), when administered to healthy subjects receiving alcohol to achieve a blood concentration of 80-100mg/100mL, FYCOMPA consistently impaired simple psychomotor performance after single doses of 4 to 12 mg, and after 21 days of multiple 12 mg/day doses. The effects of FYCOMPA on complex tasks such as driving ability were additive or supra-additive to the impairment effects of alcohol. FYCOMPA enhanced the effects of alcohol on vigilance and alertness, and increased levels of anger, confusion, and depression.
Potential to Prolong QT Interval
In a placebo-controlled thorough QT study perampanel in healthy subjects, there was no evidence that perampanel caused QT interval prolongation of clinical significance at doses of 6 or 12 mg (i.e., the upper bound of the 95% confidence interval for the largest placebo-adjusted baseline-corrected QTc was below 10 msec). The exposures observed with the 12 mg dose in this study will not cover the exposures expected in patients with hepatic impairment taking doses over 6 mg/day. At the maximum recommended dose (12 mg), perampanel did not prolong the QTc interval to any clinically relevant extent.
Pharmacokinetics of perampanel are similar in healthy subjects and patients with partial-onset seizures. The half-life of perampanel is about 105 hours, so that steady state is reached in about 2-3 weeks. AUC of perampanel increased in a dose-proportional manner after single-dose administration of 0.2–12 mg and after multiple-dose administration of 1-12 mg once daily.
Perampanel is rapidly and completely absorbed after oral administration with negligible first-pass metabolism. Median Tmax ranged from 0.5 to 2.5 hours under fasted condition. Food does not affect the extent of absorption (AUC), but slows the rate of absorption. Under fed conditions, Cmax of perampanel was decreased by 28-40% and Tmax was delayed by 2-3 hours compared to that under fasted conditions.
Data from in vitro studies indicate that, in the concentration range of 20 to 2000 ng/mL, perampanel is approximately 95-96% bound to plasma proteins, mainly bound to albumin and α1-acid glycoprotein. Blood to plasma ratio of perampanel is 0.55-0.59.
Perampanel is extensively metabolized via primary oxidation and sequential glucuronidation. Oxidative metabolism is mediated by CYP3A4 and/or CYP3A5 based on results of in vitro studies using recombinant human CYPs and human liver microsomes. Other CYP enzymes may also be involved.
Following administration of radiolabeled perampanel, unchanged perampanel accounted for 74-80% of total radioactivity in systemic circulation, whereas only trace amounts of individual perampanel metabolites were detected in plasma.
Following administration of a radiolabeled perampanel dose to 8 healthy elderly subjects, 22% of administered radioactivity was recovered in the urine and 48% in the feces. In urine and feces, recovered radioactivity was primarily composed of a mixture of oxidative and conjugated metabolites. Population pharmacokinetic analysis of pooled data from 19 Phase 1 studies reported that t1/2 of perampanel was 105 hours on average. Apparent clearance of perampanel in healthy subjects and patients was approximately 12 mL/min.
The pharmacokinetics of perampanel following a single 1 mg dose were evaluated in 12 subjects with mild and moderate hepatic impairment (Child-Pugh A and B, respectively) compared with 12 demographically matched healthy subjects. The total (free and protein bound) exposure (AUC0-inf) of perampanel was 50% greater in subjects with mild hepatic impairment and more than doubled (2.55-fold) in subjects with moderate hepatic impairment compared to their healthy controls. The AUC0-inf of free perampanel in subjects with mild and moderate hepatic impairment was 1.8-fold and 3.3-fold, respectively, of those in matched healthy controls. The t1/2 was prolonged in subjects with mild impairment (306 vs. 125 hours) and moderate impairment (295 vs. 139 hours). Perampanel has not been studied in subjects with severe hepatic impairment [see DOSAGE AND ADMINISTRATION, Use in Specific Populations ].
A dedicated study has not been conducted to evaluate the pharmacokinetics of perampanel in patients with renal impairment. Population pharmacokinetic analysis was performed on pooled data from patients with partial-onset seizures and receiving FYCOMPA up to 12 mg/day in placebo-controlled clinical trials. Results showed that perampanel apparent clearance was decreased by 27% in patients with mild renal impairment (creatinine clearance 50-80 mL/min) compared to patients with normal renal function (creatinine clearance > 80 mL/min), with a corresponding 37% increase in AUC. Considering the substantial overlap in the exposure between normal and mildly impaired patients, no dosage adjustment is necessary for patients with mild renal impairment. Perampanel has not been studied in patients with severe renal impairment and patients undergoing hemodialysis [see DOSAGE AND ADMINISTRATION, Use in Specific Populations].
In a population pharmacokinetic analysis of patients with partial-onset seizures receiving FYCOMPA in placebo-controlled clinical trials, perampanel apparent clearance in females (0.605 L/hr) was 17% lower than in males (0.730 L/hr). No dosage adjustment is necessary based on sex.
FYCOMPA has not been studied in patients < 12 years old. In a population pharmacokinetic analysis of patients with partial-onset seizures ranging in age from 12 to 74 years receiving FYCOMPA in placebo-controlled trials, apparent clearance of perampanel in adolescents (0.787 L/hr) was slightly, but not significantly, higher than that in adults. Pediatric patients above 12 years old can be dosed similarly to adults.
In a population pharmacokinetic analysis of patients with partial-onset seizures ranging in age from 12 to 74 years receiving FYCOMPA in placebo-controlled trials, no significant effect of age on perampanel apparent clearance was found [see DOSAGE AND ADMINISTRATION, Use in Specific Populations].
In a population pharmacokinetic analysis of patients with partial-onset seizures which included 576 Caucasians, 14 Blacks, 97 non-Chinese Asians, and 62 Chinese receiving FYCOMPA in placebo-controlled trials, no significant effect of race on perampanel apparent clearance was found. No dosage adjustment is necessary.
Drug Interaction Studies
In Vitro Assessment of Drug Interactions
Drug Metabolizing Enzymes
In human liver microsomes, perampanel at a concentration of 30 μmol/L, about 10 fold the steady state Cmax at a 12 mg dose, had a weak inhibitory effect on CYP2C8, CYP3A4, UGT1A9 and UGT2B7. Perampanel did not inhibit CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, UGT1A1, UGT1A4 and UGT1A6 at a concentration of 30 μmol/L.
Compared with positive controls (including phenobarbital and rifampin), perampanel was found to weakly induce CYP2B6 (30μmol/L) and CYP3A4/5 ( ≥ 3μmol/L) in cultured human hepatocytes. Perampanel also induced UGT1A1 ( ≥ 3μmol/L) and UGT1A4 (30μmol/L). Perampanel did not induce CYP1A2 at concentrations up to 30 μmol/L.
In vitro studies showed that perampanel is not a substrate or significant inhibitor of the following: organic anion transporting polypeptides 1B1 and 1B3; organic anion transporters 1, 2, 3, and 4; organic cation transporters 1, 2, and 3; efflux transporters P-glycoprotein and Breast Cancer Resistance Protein.
In Vivo Assessment of Drug Interactions
Drug Interactions with AEDs
Effect of concomitant AEDs on FYCOMPA:
Carbamazepine. As an inducer of CYP enzymes, carbamazepine increases perampanel clearance. Steady state administration of carbamazepine at 300 mg BID in healthy subjects reduced the Cmax and AUC0-inf of a single 2 mg dose of perampanel by 26% and 67% respectively. The t1/2 of perampanel was shortened from 56.8 hours to 25 hours. In clinical studies examining partial-onset seizures, a population pharmacokinetic analysis showed that perampanel AUC was reduced by 67% in patients on carbamazepine compared to the AUC in patients not on enzyme-inducing AEDs [see DOSAGE AND ADMINISTRATION, DRUG INTERACTIONS].
Oxcarbazepine. In clinical studies examining partial-onset seizures, a population pharmacokinetic analysis showed that perampanel AUC was reduced by half in patients on oxcarbazepine compared to patients not on enzyme-inducing AEDs [see DOSAGE AND ADMINISTRATION, DRUG INTERACTIONS].
Phenytoin. In clinical studies examining partial-onset seizures, a population pharmacokinetic analysis showed that perampanel AUC was reduced by half in patients on phenytoin compared to patients not on enzyme-inducing AEDs [see DOSAGE AND ADMINISTRATION, DRUG INTERACTIONS].
Phenobarbital and Primidone: In a population pharmacokinetic analysis of patients with partial-onset seizures in clinical trials (37 patients co-administered phenobarbital and 9 patients co-administered primidone) no significant effect on perampanel AUC was found. A modest effect of phenobarbital and primidone on perampanel concentrations cannot be excluded.
Topiramate: Population pharmacokinetic analysis of patients with partial-onset seizures in clinical trials showed that perampanel AUC was reduced by approximately 20% in patients on topiramate compared to patients not on enzyme-inducing AEDs.
Other AEDs: Population pharmacokinetic analysis of patients with partial-onset seizures in clinical trials showed that clobazam, clonazepam, lamotrigine, levetiracetam, valproate, and zonisamide did not have an effect on perampanel clearance.
Other strong CYP3A inducers (e.g., rifampin, St. John's wort) may also greatly increase clearance of perampanel and reduce perampanel plasma concentrations [see DRUG INTERACTIONS].
Effect of FYCOMPA on concomitant AEDs:
FYCOMPA up to 12 mg/day did not significantly affect the clearance of clonazepam, levetiracetam, phenobarbital, phenytoin, topiramate, or zonisamide based on a population pharmacokinetic analysis of patients with partial-onset seizures in clinical trials. FYCOMPA had a statistically significant effect on the clearance of carbamazepine, clobazam, lamotrigine, and valproic acid, but the increases in clearance of these drugs were each less than 10% at the highest perampanel dose evaluated (12 mg/day). FYCOMPA co-administration resulted in a 26% decrease in oxcarbazepine clearance and increased its concentrations. The concentrations of 10-monohydroxy metabolite (MHD), the active metabolite of oxcarbazepine, were not measured.
Drug-drug interaction studies with other drugs
Effect of other drugs on FYCOMPA
Ketoconazole. Co-administration of single 1-mg dose of perampanel with 400 mg once daily doses of ketoconazole, a strong CYP3A4 inhibitor, for 8 days in healthy subjects prolonged perampanel t1/2 by 15% (67.8 vs. 58.4 hours) and increased AUC0-inf by 20%.
Oral contraceptives. Perampanel Cmax and AUC0-72h were not altered when a single 6-mg dose of perampanel was administered to healthy female subjects following a 21-day course of oral contraceptives containing ethinylestradiol 30 μg and levonorgestrel 150 μg.
Effect of FYCOMPA on other drugs
Midazolam. Perampanel administered as 6 mg once daily doses for 20 days decreased AUC0-inf and Cmax of midazolam (a CYP3A4 substrate) by 13% and 15%, respectively, in healthy subjects.
Oral Contraceptives. Co-administration of perampanel 4 mg once daily with an oral contraceptive containing ethinylestradiol 30 μg and levonorgestrel 150 μg for 21 days did not alter Cmax or AUC0-24h of either ethinylestradiol or levonorgestrel in healthy female subjects. In another study, a single dose of the oral contraceptive was administered following 21-day once daily dosing of FYCOMPA 12 mg or 8 mg in healthy females. FYCOMPA at 12 mg did not alter AUC0-24h of ethinylestradiol but decreased its Cmax by 18%, and also decreased Cmax and AUC0-24h of levonorgestrel by 42% and 40%, respectively. FYCOMPA at 8 mg did not have significant effect on Cmax or AUC0-24h of either ethinylestradiol or levonorgestrel, with a small decrease in AUC0-24h of levonorgestrel (9%) [see DRUG INTERACTIONS].
Levodopa. Perampanel administered as 4 mg once daily doses for 19 days had no effect on Cmax and AUC0-inf of levodopa in healthy subjects.
The efficacy of FYCOMPA in partial-onset seizures, with or without secondary generalization, was studied in patients who were not adequately controlled with 1 to 3 concomitant AEDs in 3 randomized, double-blind, placebo-controlled, multicenter trials (Studies 1, 2, and 3) in adult and adolescent patients (aged 12 years and older). All trials had an initial 6-week Baseline Period, during which patients were required to have more than five seizures in order to be randomized. The Baseline Period was followed by a 19 week Treatment Period consisting of a 6 week Titration Phase and a 13 week Maintenance Phase. Patients in these 3 trials had a mean duration of epilepsy of approximately 21 years and a median baseline seizure frequency ranging from 9.3 to 14.3 seizures per 28 days. During the trials, more than 85% of patients were taking 2 to 3 concomitant AEDs with or without concurrent vagal nerve stimulation, and approximately 50% were on at least one AED known to induce CYP3A4, an enzyme critical to the metabolism of FYCOMPA (i.e. carbamazepine, oxcarbazepine, or phenytoin), resulting in a significant reduction in FYCOMPA's serum concentration [see DRUG INTERACTIONS, CLINICAL PHARMACOLOGY].
Each study evaluated placebo and multiple FYCOMPA dosages (see Figure 1). During the Titration period in all 3 trials, patients on FYCOMPA received an initial 2 mg once daily dose, which was subsequently increased in weekly increments of 2 mg per day to the final target dose. Patients experiencing intolerable adverse reactions were permitted to have their dose reduced to the previously tolerated dose.
The primary endpoint in Studies 1, 2, and 3 was the percent change in seizure frequency per 28 days during the Treatment Period as compared to the Baseline Period. The criterion for statistical significance was p < 0.05. Table 3 shows the results of these studies. A statistically significant decrease in seizure rate was observed at doses of 4 to 12 mg per day. Dose response was apparent at 4 to 8 mg with little additional reduction in frequency at 12 mg per day.
Table 3: Median Treatment Difference (Drug - Placebo) of the Percent
Reduction from Baseline during the 19-Week Treatment Period.
|Dosage Group||n||Median Baseline Frequency (per 28 days)||Median Treatment Effect (Drug-Placebo)||p value|
|8 mg/day||169||10.9||-20.10%||< 0.0001|
Table 4 presents an analysis combining data from all 3 studies, grouping patients based upon whether or not concomitant AED inducers (carbamazepine, oxcarbazepine, or phenytoin) were used. The analysis revealed a substantially reduced effect in the presence of inducers.
Table 4: Median Treatment Effect (drug -
placebo) for Combined Studies (Study 1, 2 and 3) Based on the Presence or
Absence of Concomitant FYCOMPA Inducing AEDs (carbamazepine, oxcarbazepine,
|Median Percent Reduction From Placebo||Responder Rateb (Drug – Placebo)|
|Without Inducers||With Inducers||Without Inducers||With Inducers|
from Latin American region are excluded because of a significant
treatment-by-region interaction due to high placebo response.
bThe proportion of patients with at least a 50% decrease in seizure frequency
Figure 1 shows the proportion of patients with different percent reductions during the maintenance phase over baseline across all three trials. Patients in whom the seizure frequency increased are shown at left as “worse.” Patients in whom the seizure frequency decreased are shown in the remaining five categories. Thus, the percentages of patients with a 40 to < 60% reduction in seizure frequency were 13.2%, 17.4%, 19.0%, and 15.8% for placebo, 4, 8, and 12 mg, respectively.
Figure 1: Proportion of Patients
Exhibiting Different Percent Reductions During the Maintenance Phase over
Baseline Across All Three Trials.
The percentages of patients with a 50% or greater reduction in seizure frequency were 19.3%, 28.5%, 35.3%, 35.0% for placebo, 4, 8, and 12 mg, respectively.
Last reviewed on RxList: 11/1/2012
This monograph has been modified to include the generic and brand name in many instances.
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