Fycompa - Pharmaceutical Information, Clinical Trials, Detailed Pharmacology, Toxicology.
Россия
  • Россия
  • Украина

Fycompa - Scientific Information

Manufacture: Eisai Inc.
Country: Canada
Condition: Epilepsy, Seizures (Convulsions)
Class: AMPA receptor antagonists, Anticonvulsants
Form: Tablets
Ingredients: perampanel, lactose monohydrate, giproloza low substituted, povidone, magnesium stearate, MCC

Pharmaceutical Information

Drug Substance

Proper name: perampanel
Chemical name: 2-(2-oxo-1-phenyl-5-pyridin-2-yl-1,2-dihydropyridin-3-yl) benzonitrile hydrate (4:3)
Molecular formula: C23H15N3O • ¾ H2O
Molecular mass: 362.90 (3/4 hydrate)
Structural formula:



Physicochemical properties: Perampanel is a white to yellowish white powder. It is freely soluble in N-methylpyrrolidone, sparingly soluble in acetonitrile and acetone, slightly soluble in methanol, ethanol and ethyl acetate, very slightly soluble in 1-octanol and diethyl ether and practically insoluble in heptane and water.

Clinical Trials

Partial-Onset Seizures

Study Demographics and Trial Designs

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 304, 305 and 306). The total number of FYCOMPA-treated patients was 1038. 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 CYP3A, an enzyme family 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, Interactions between FYCOMPA and other anti-epileptic drugs (AEDs)). Concomitant AEDs taken by at least 10% of the subjects in the total placebo and perampanel group were: carbamazepine (34%), lamotrigine (32%), valproic acid (31%), levetiracetam (30%), topiramate (20%), oxcarbazepine (18%) and clobazam (11%).

Each study evaluated placebo and multiple FYCOMPA dosages (see Table 5). During the Titration Period in all 3 trials, patients on FYCOMPA received an initial 2 mg once daily dose, which was subsequently increased by 2 mg at weekly increments to reach the final target dose. Patients experiencing intolerable adverse reactions with dose increases were permitted to remain in the study at a reduced dose.

The primary endpoint in Studies 304, 305, and 306 was the percent change in partial-onset seizure frequency per 28 days during the Treatment Period as compared to the Baseline Period.

Study Results

A statistically significant decrease in seizure rate was observed at doses of 4 to 12 mg per day (see Table 1). Dose response was apparent at 4 to 8 mg with little additional reduction in seizure frequency at 12 mg per day. Results of the 50% Responder Rates also support the results of the primary efficacy endpoint.

Table 1: Summary: Median Percent Reduction in 28-day Total Partial Seizure Frequency from Baseline over the double-blind Treatment Phase (primary efficacy end-point) and of Responder Rates in the Maintenance Phase (secondary endpoint)
Study
n=population in double-blind phase
AEDs +
Placebo
AEDs + FYCOMPA
2mg/day 4mg/day 8mg/day 12mg/day
Study 304
Median Baseline Seizure Frequency 13.7 14.3 12
n 121 133 133
Median % Reduction 21% 26%* 35%*
50% Responder rate1 26% 38% 36%
Study 305
Median Baseline Seizure Frequency 11.8 13 13.7
n 136 129 121
Median % Reduction 10% 31%*** 18%*
50% Responder rate1 15% 33%** 34%***
Study 306
Median Baseline Seizure Frequency 9.3 10.1 10 10.9
n 184 180 172 169
Median % Reduction 11% 14% 23%** 31%***
50% Responder rate1 18% 21% 29%* 35%***
Combined Studies (Study 304, 305 and 306)
Median Baseline Seizure Frequency 11.1 10.1 10.0 12.2 13.0
n 441 180 172 431 254
Median % Reduction 13% 14% 23% 29% 27%
50% Responder rate1 19% 21% 29% 35% 35%

–Dose not studied

*, **, *** for p<0.05, p<0.01 and p < 0.001 (p-value not shown for combined studies)

150% Responder rate = percentage of patients with ≥50% reduction in 28-day total seizure frequency from Baseline to the Maintenance Phase

Table 2 presents an analysis combining data from all 3 studies, grouping patients based upon whether or not concomitant CYP3A enzyme-inducers AEDs (EI-AEDs) were used. The analysis revealed a reduced treatment effect in the presence of concomitant EI-AEDS.

Table 2: Median Treatment Effect for Combined Studies (Study 304, 305 and 306) Based on the Presence or Absence of Concomitant CYP3A-Inducing AEDs (carbamazepine, oxcarbazepine, phenytoin)*
Median Percent Reduction Responder Rate**
Without Inducers With Inducers Without Inducers With Inducers
Placebo n=441 13% 8% 17% 18%
2 mg/day n=180 18% 8% 23% 19%
4 mg/day n=172 21% 25% 34% 24%
8 mg/day n=431 44% 23% 47% 28%
12 mg/day n=254 39% 18% 47% 30%

* Patients from Latin America region excluded because of significant treatment-by-region interaction due to high placebo response.

**The proportion of patients with at least a 50% decrease in seizure frequency.

There were no significant differences in seizure control as a function of gender.

Primary Generalized Tonic-Clonic (PGTC) Seizures

Study Demographics and Trial Designs

The effectiveness of FYCOMPA as adjunctive therapy in patients with idiopathic generalized epilepsy experiencing primary generalized tonic-clonic seizures (PGTC) was assessed in one multicenter, randomized, double-blind, placebo-controlled study. Eligible patients on a stable dose of 1 to 3 AEDs experiencing at least 3 primary generalized tonic-clonic seizures during the 8-week Baseline Period were randomized to either FYCOMPA (n=81) or placebo (n=81).

The Baseline Period was followed by a 17 week Treatment Period, consisting of a 4 week Titration Phase and 13 week Maintenance Phase.

Patients had a mean duration of epilepsy of approximately 17 years. Approximately 30% of the patients experienced only PGTC seizures; the remaining patients experienced one or more seizures types in addition to tonic-clonic. Absence seizures were reported by 50% of the patients, and myoclonic seizures by 40%. With respect to the number of concomitant AEDS taken at baseline, the frequency distribution was similar for the two treatment groups: approximately 30% were taking only 1 AED; 50% were taking 2; and 20% were taking 3 AEDs. For a total of 27 patients, these included an enzyme-inducing AED (11% in the perampanel group, 22.0% in the placebo group).

Patients were titrated over 4 weeks up to a maximum dose of 8 mg per day or the highest tolerated dose.

The primary efficacy endpoint was the percent change in primary generalized tonic-clonic seizure frequency per 28 days during the Treatment Period as compared to the Baseline Period.

Study results

A statistically significant decrease in seizure rate was observed with FYCOMPA compared to placebo (Table 3). Results of the 50% Responder Rates also support the results of the primary efficacy endpoint.

Table 3: Median Percent Reduction in 28-day Total PGTC Seizure Frequency from Baseline over the double-blind Treatment Phase (primary efficacy end-point), with Responder Rates in the Maintenance Phase (secondary endpoint)
AEDs +
Placebo
(N=81)
AEDs +
FYCOMPA
(N=81)
Median Baseline Seizure Frequency 2.5 2.6
Median % Reduction 38% 76%а
50% Responder Rateb 40% 64%

aP-value compared to placebo: <0.0001

bThe proportion of patients with at least a 50% decrease in seizure frequency.

Pediatrics (< 18 years of age):

The safety and efficacy of FYCOMPA in pediatric patients have not been established and its use in this patient population is not indicated.

Detailed Pharmacology

The results of in vitro testing suggest that perampanel is a selective, non-competitive antagonist of the ionotropic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic 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. While the data suggest that perampanel is selective for the AMPA receptor, they are not sufficient to rule out other pharmacological activity.

In vitro,perampanel did not compete with AMPA for binding to the AMPA-type glutamate receptor, and perampanel binding to rat forebrain membranes was displaced by noncompetitive AMPA receptor antagonists, indicating that perampanel is a noncompetitive AMPA receptor antagonist. In cultured rat cortical neurons, perampanel inhibited AMPA-induced (but not NMDA-induced) increase in intracellular calcium. Perampanel neither inhibited nor potentiated GABA-evoked current in cells expressing different human recombinant GABAA receptor subtypes.

Preclinical Pharmacodynamics

In vivo,perampanel showed potent anticonvulsant activities in several animal models of seizures. Perampanel protected mice from generalized tonic-clonic seizures in an audiogenic seizure model and the maximal electroshock seizure mode, with ED50 values of 0.47 mg/kg and 1.6 mg/kg respectively. Perampanel also protected mice from myoclonic seizures in the pentylenetetrazol-induced seizure model with an ED50 value of 0.94 mg/kg. Perampanel significantly prolonged seizure latency in an AMPA-induced seizure model in mice. In the amygdala kindling model in rats, perampanel significantly elevated the afterdischarge threshold and reduced seizure severity and afterdischarge duration. In a mouse corneal kindling model, oral perampanel delayed or abolished the kindling development. Perampanel showed no antiepileptic activity in the genetic model of absence epilepsy in the rat.

Preclinical Safety Pharmacology

Perampanel had no effects on heart rate, blood pressure or electrocardiogram (ECG) parameters, including QT intervals in conscious dogs at oral doses up to 10 mg/kg. Estimated IC50 value for perampanel block of human ether-à-go-go related gene (hERG) tail current was 15.8 μmol/L (5.52 μg/mL). The highest plasma concentration of perampanel in clinical use was estimated to be approximately 2 μg/mL with a free drug concentration adjusted for protein binding of approximately 90 ng/mL based on data from clinical trials. The free drug concentration (90 ng/mL) is approximately 60-times lower than the estimated IC50 value for the hERG inhibition (5.5 μg/mL).

In a physical dependence study in rats, low-dose (14.7 mg/kg/day) and high-dose (43.5 mg/kg/day) perampanel was administered by dietary admixture for four weeks, followed by a 1-week withdrawal period. During the withdrawal period, animals in both treated groups showed mild signs of withdrawal such as hyperreactivity to handling and muscle rigidity, decreases in food consumption and body weight loss. In a self-administration study in monkeys, results suggested that perampanel had a reinforcing effect without causing physical withdrawal symptoms when intravenously self-administered in rhesus monkeys. From this study, the potency of reinforcing effects of perampanel was considered positive but not strong. The results suggest that perampanel may have the potential to cause dependence, both physical and psychological.

In the rotarod test in mice and rats, oral administration of perampanel dose-dependently induced motor-incoordination. ED50 values were 1.8 mg/kg in mice and 9.14 mg/kg in rats.

Toxicology

Repeated Dose Toxicity

Maximum tolerated dose (MTD) administration to rats (100 mg/kg/day in males and 30 mg/kg/day in females) for 13 or 26 weeks and in cynomolgus monkeys (8 mg/kg/day in both sexes) for 39 weeks resulted in severe pharmacologically-based CNS clinical signs and decreased terminal body weight. There were no changes directly attributable to perampanel in clinical pathology or histopathology. The systemic exposures (Cmax and AUC) at MTD were approximately equivalent or lower than the exposures in human at the maximum recommended human dose (MRHD) of 12 mg per day.

In oral repeated-dose toxicity studies of 4 to 52 weeks, the primary finding in all species was effects on CNS, including abnormal gait, reduced motor activity and/or prostration were observed in all species. In studies of up to 13 weeks in mice, these CNS clinical signs were accompanied by decreases in body weight gains and food consumption. In oral repeated dose toxicity studies for up to 26 weeks in rats, CNS clinical signs and decreases in body weight gain and food consumption were observed at 30 mg/kg and 60 mg/kg. In studies of up to 13 weeks in dogs, CNS clinical signs were observed at 1 mg/kg and higher. In studies in cynomolgus monkeys for up to 52 weeks, clinical signs such as ataxic gait; decreased activity, sitting position, and transient prostration were observed. Death due to severe adverse clinical signs occurred at the highest dose tested (8 mg/kg) in the 39−week study. The observed CNS clinical signs of abnormal gait, reduced motor activity and/or prostration are not unexpected findings for an AMPA antagonist. These dosage-related clinical signs were mainly related to Cmax, and were observed in general when Cmax approached approximately 1400 ng/mL (10 – 30 mg/kg) in mice, 500 ng/mL (10 – 30 mg/kg) in rats, 80 ng/mL (1 mg/kg) in dogs, and 300 ng/mL (1 mg/kg) in monkeys. There was no organ toxicity or histopathologic findings at any dose in any of the species.

Clinical signs consistent with excessive grooming/scratching and/or self-mutilation were observed in the adult mouse, rat and rabbit, and in the juvenile rat and dog. It remains unclear whether the apparent self-mutilation is an extension of the excessive grooming or a separate behavioural effect. It is primarily in the juvenile animals that the actual behaviour of excessive grooming was observed; otherwise, it was generally inferred from the injuries. Mortality due to skin lesions attributed to excessive grooming was observed at 60 mg/kg and higher in repeateddose toxicity studies in mice. Deaths or morbidity occurred in rats after severe clinical signs including excessive grooming and self-mutilation in males given 100 mg/kg and higher and in females given 30 mg/kg and higher. In the carcinogenicity study in the mouse, similar clinical signs including loss of fore-hind limbs and loss of digits were observed at doses of > 3mg/kg/day. “Increase in grooming” was observed in adult rats and rabbits in reproductive studies, accompanied by “swelling of limbs” in the rat. “Excessive scratching” was observed at all doses in studies of the juvenile rat and dog. “Excessive grooming” was observed in a 13-week phototoxicity study in hairless mice. The clinical relevance of these data to humans is unknown.

Carcinogenesis and Mutagenesis

Perampanel was administered orally to mice (1, 3, 10, or 30 mg/kg/day) and rats (10, 30, or 100 mg/kg/day in males; 3, 10, or 30 mg/kg/day in females) for up to 104 weeks. There was no evidence of drug-related tumors in either species. Plasma perampanel exposures (AUC) at the highest doses tested were less than that in humans dosed at 8 mg/day.

Perampanel was negative in the in vitro Ames and mouse lymphoma assays, and in the in vivo rat micronucleus assay.

Development and Reproductive Studies

In male and female rats administered perampanel (oral doses of 1, 10, or 30 mg/kg/day) prior to and throughout mating and continuing in females to gestation day 6, there were no clear effects on fertility. Prolonged and/or irregular estrus cycles were observed at all doses but particularly at the highest dose tested. Plasma perampanel exposures (AUC) at all doses were lower than that in humans dosed at 8 mg/day.

In animal studies, perampanel induced developmental toxicity in pregnant rat and rabbit at clinically relevant doses. Oral administration of perampanel (1, 3, or 10 mg/kg/day) to pregnant rats throughout organogenesis resulted in an increase in visceral abnormalities (diverticulum of the intestine) at all doses tested. In a dose-ranging study at higher oral doses (10, 30, or 60 mg/kg/day), embryo lethality and reduced fetal body weight were observed at the mid and high doses tested. The lowest dose tested (1 mg/kg/day) is similar to a human dose of 8 mg/day based on body surface area (mg/m2).

Upon oral administration of perampanel (1, 3, or 10 mg/kg/day) to pregnant rabbits throughout organogenesis, embryo lethality was observed at the mid and high doses tested; the no effect dose for embryo-fetal developmental toxicity in rabbit (1 mg/kg/day) is approximately 2 times a human dose of 8 mg/day based on body surface area (mg/m2).

Oral administration of perampanel (1, 3, or 10 mg/kg/day) to rats throughout gestation and lactation resulted in fetal and pup deaths at the mid and high doses and delayed sexual maturation in males and females at the highest dose tested. No effects were observed on measures of neurobehavioural or reproductive function in the offspring. The no-effect dose for pre- and postnatal developmental toxicity in rat (1 mg/kg/day) is similar to a human dose of 8 mg/day based on body surface area (mg/m2).