29
CHAPTER
Newest Antiepileptic Drugs and Drugs in Development
K. Nicole Mims and Aatif M. Husain
Despite the approval of many new antiepileptic drugs (AEDs) in the past 20 years, there are a sizable number of patients with epilepsy whose seizures remain refractory to medical therapy. There are a number of AEDs that are in various stages of development, and there is hope that these medications will provide more effective therapy with fewer adverse effects. The list of medications that are in development is constantly changing as some receive approval by regulatory agencies, while others are deemed not to be effective or provide a substantial improvement over currently available therapies. In this chapter, a few of these AEDs will be discussed. One of the medications discussed, eslicarbazepine, has recently received approved by the U.S. Food and Drug Administration (FDA). Brivaracetam and ganaxolone are in different stages of drug development. A summary of these agents is presented in Table 29.1 (located at the end of the chapter). There are several others as well, and the interested reader is referred to excellent resources that discuss these agents (1,2).
ESLICARBAZEPINE
Indications
Eslicarbazepine was recently approved by the FDA as adjunctive treatment of partial-onset seizures. Though not specifically stated, it is currently approved for use in adults. Pediatric safety data are not yet available.
Dosing
Eslicarbazepine dosing should start at 400 mg/day. The dose can be increased by 400 mg every week to a maximum of 1,200 mg/day. The recommended daily dose is 800 mg, but it is recognized that some patients may need the higher dose. Side effects are more common at the higher dose. An investigation of twice-daily dosing of eslicarbazepine revealed a 33% lower concentration of eslicarbazepine when dosed twice daily as compared to once daily (3).
Pharmacology
The exact mechanism of antiepileptic effect of eslicarbazepine is not known. However, it is thought that eslicarbazepine acts as a voltage-gated sodium channel blocker, which uniquely targets inactive sodium channels that have recently been open. This mechanism of action is theorized to allow eslicarbazepine to specifically target rapidly firing neurons.
Eslicarbazepine is available commercially as eslicarbazepine acetate. After absorption, eslicarbazepine acetate is virtually undetectable and is rapidly converted to eslicarbazepine. Eslicarbazepine exerts the antiepileptic effect. The Cmax is achieved 1 to 4 hours post dose. The half-life is 13 to 20 hours and steady state is achieved in 4 to 5 days. Food does not affect absorption. Protein binding of eslicarbazepine is low, and thus does not affect many other drugs that are highly plasma protein bound. Eslicarbazepine is metabolized with first-pass metabolic hydrolysis primarily to S-licarbazepine. Approximately 5% of eslicarbazepine is metabolized to oxcarbazepine and R-licarbazepine. Contrary to its parent drugs, carbamazepine and oxcarbazepine, eslicarbazepine is not metabolized by the CYP system in the liver and is neither an inducer nor inhibitor of liver enzymes. Approximately one third of the metabolites undergo glucuronidation and the remainder is excreted unchanged. Elimination occurs via the kidneys.
Efficacy Data
Four multicenter, double-blind, randomized, placebo-controlled trials were conducted to evaluate efficacy and safety of eslicarbazepine for treatment of adjunctive therapy in patients with refractory partial-onset epilepsy (3–6). Of these four trials, one trial focused on once-daily versus twice-daily dosing, finding decreased plasma concentration of eslicarbazepine in the twice-daily dosing group as mentioned earlier (3). The other three trials shared similar methodology with a baseline period during which seizure frequency was monitored, a brief titration period usually lasting a few weeks and then a 14- to 18-week treatment period. All evaluated 800 mg and 1,200 mg/day dosing with two studies including 400 mg/day and one including 200 mg/day. All trials demonstrated decreased seizure frequency in the 800 mg and 1,200 mg/day treatment groups (35% and 39%, respectively) compared to placebo (15%), and there was no significant difference between the two doses (7).
Efficacy in Other Conditions
Eslicarbazepine is FDA approved for only partial-onset seizures. However, studies are underway for its use treating in bipolar disorder and various pain syndromes. The pain syndromes that are being studied include fibromyalgia, postherpetic neuralgia, and painful diabetic neuropathy. Details of efficacy in these disorders are not yet available.
Adverse Effects
The most common adverse events seen with eslicarbazepine are central nervous system (CNS) related and similar to those of other AEDs. The most common side effects are dizziness, somnolence, headache, and nausea. A relatively common unique side effect of eslicarbazepine is diplopia. Psychiatric side effects that may be seen include depression, agitation, and apathy. Rash has been reported as well, but when seen in clinical trials, it resolved with discontinuation of the medication. Hyponatremia has been reported as well, but the incidence is much lower than observed with carbamazepine or oxcarbazepine. It should be noted, however, that in the clinical trials, withdrawals occurred in up to 19% and 27% of the 800 mg and 1,200 mg/day groups compared to up to 7% with the placebo group (8).
Toxicity, Overdose, and Contraindications
Acute toxicology studies revealed the estimated lethal dose of eslicarbazepine in the mouse and rat was 500 mg/kg when administered orally and 100 mg/kg when administered intravenously. Human toxicity levels are not known. The treatment of overdose is supportive. Gastric lavage and the use of activated charcoal should be considered. Eslicarbazepine is contraindicated in patients who have had an allergic reaction to oxcarbazepine.
Warning and Precautions
Eslicarbazepine should be used with caution in patients with 2nd or 3rd degree atrioventricular (AV) heart block. This caution results from an increase in the PR interval on electrocardiograms (ECG) seen especially in patients taking 1,200 mg/day.
Teratogenicity
Eslicarbazepine is a Pregnancy Category C AED. There are no adequately controlled human teratogenicity studies. Use of this AED in pregnancy should clearly outweigh the potential known risk. Eslicarbazepine is excreted in breast milk, and caution is advised when used in women who are breastfeeding.
Special Safety Concerns
As with all other AEDs, suicidal behavior and ideation is a concern. However, this is no more a concern than with other AEDs. Serious skin rashes have been reported, including Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). In addition, multiorgan hypersensitivity, anaphylactic reactions, and angioedema have also been reported. Clinically significant hyponatremia (sodium <125 mEq/L) has been reported, but as noted earlier, it appears to be less common than with carbamazepine and oxcarbazepine.
Drug Interactions
Eslicarbazepine interacts with various AEDs. When combined with phenytoin and phenobarbital, eslicarbazepine serum concentration is reduced. Although eslicarbazepine failed to demonstrate any interaction with carbamazepine or oxcarbazepine, this combination resulted in significantly increased incidence of diplopia, abnormal coordination, and dizziness.
Eslicarbazepine significantly increases the elimination rate of both hormonal components in oral contraceptives and can result in contraceptive failure. Although no effect is seen on anticoagulation, eslicarbazepine can result in decreased exposure of warfarin (8). Anticoagulation status should be carefully monitored in these patients.
Use in Special Populations
Eslicarbazepine should be avoided in pregnancy and nursing mothers since its effects have not been assessed in these populations. In patients with renal impairment, clearance is decreased and total exposure increased. Reducing the eslicarbazepine dose is recommended in patients with severe renal impairment, but dose adjustment in mild or moderate renal impairment has not yet been elucidated. Dose adjustments are not necessary for mild or moderate hepatic impairment, but eslicarbazepine should not be used in patients with severe hepatic impairment.
Pediatric Use
Eslicarbazepine has not been tested in pediatrics and use in this population is not currently recommended.
BRIVARACETAM
Indications
Brivaracetam is not currently approved by the FDA. Clinical trials have been performed in adults and children as adjunctive therapy for partial-onset and generalized seizures.
Dosing
The dosing of brivaracetam has been investigated in several clinical trials in adults. Earlier studies investigated lower doses ranging from 10 mg/day to 80 mg/day. In these studies, higher doses of 50 mg/day and 80 mg/day were more effective than lower doses and placebo (9–11). Subsequent studies investigated higher doses up to 200 mg/day (2,12,13). Higher doses appeared to be more effective. The final recommended dose has not yet been determined.
Pharmacology
Brivaracetam is a drug derivative of levetiracetam and as such shares levetiracetam’s mechanism of action on synaptic vesicle protein 2A (SV2A). Brivaracetam’s affinity for SV2A is estimated to be 25 times greater than that of levetiracetam. How binding to SV2A exerts antiepileptic effects is not known. It is thought that SV2A is involved with presynaptic exocytosis of intraneuronal vesicles. Drugs that bind to SV2A may disrupt this process and reduce excitatory neurotransmission. In addition, brivaracetam also inhibits neuronal voltage-dependent sodium channels (14).
Brivaracetam exhibits linear pharmacokinetics and is rapidly absorbed after oral administration. It is not highly protein bound (less than 20%) and has an average half-life of 7 to 8 hours, necessitating at least twice-daily dosing. It is extensively metabolized by hydrolysis via the cytochrome P450 system. The metabolites are inactive. Over 95% of the brivaracetam metabolites are excreted in urine (11).
Efficacy Data
Several clinical trials documented the efficacy of brivaracetam in adults. Two Phase IIb and three Phase III trials have been completed assessing efficacy of brivaracetam as adjunctive therapy in patients with refractory partial-onset epilepsy or generalized epilepsies in adults (9–13). In one of the Phase IIb studies, doses of 5 mg/day, 20 mg/day, and 50 mg/day were compared to placebo. Only the 50 mg/day dose resulted in statistically significant reduction of seizure frequency compared to placebo (10). The other Phase IIb study evaluated 50 mg/day and 150 mg/day of brivaracetam compared to placebo. Neither dose resulted in statistically significant reduction in seizure frequency as compared to placebo (11).
Results from two of the Phase III studies have been published. In one study, 5 mg/day, 20 mg/day, and 50 mg/day doses were compared to placebo. Much like the Phase IIb study, in this study only the 50 mg/day dose resulted in a significantly lower (22%) seizure frequency/28 days compared to placebo (9). In the other Phase III study, higher doses of 50 mg/day and 100 mg/day were compared to placebo. Interestingly, the primary end point (percent reduction in seizures) was statistically significant for the 50 mg/day dose compared to placebo but not the 100 mg/day dose (13). Another Phase III study that has recently been completed evaluated up to 200 mg/day. The final recommended dose has not been established yet.
Efficacy in Other Conditions
Along with being investigated in various types of epilepsy, brivaracetam has been evaluated in postherpetic neuralgia. The results of these investigations are not yet known. The value of this medication in non-epilepsy-related conditions remains uncertain.
Adverse Effects
The most common adverse effects reported with brivaracetam are headache, somnolence, dizziness, and fatigue. Other side effects include nasopharyngitis and urinary tract infection. Serious adverse events necessitating discontinuation of medication in clinical trials were aggression, anxiety, irritability, insomnia, depression, convulsions, and dizziness (2).
Toxicity, Overdose, and Contraindications
Little information is available about brivaracetam toxicity. Transient, dose-related CNS effects were seen in toxicology studies in rats and mice, and these generally occurred above 100 mg/kg. Significant cardiac, respiratory, or gastrointestinal damage was not seen. Chronic use of high doses resulted in liver and biliary injury. In healthy volunteers, a study prescribing 1,000 mg/day or 800 mg twice daily failed to reveal any significant toxic effects and the adverse events noted were mostly CNS related. Vital signs, physical and chemical laboratory examinations remained normal. No clear contraindications exist at this time (2,14).
Warning and Precautions
No clear warnings or precautions exist currently for brivaracetam. In general, it is a well-tolerated drug even at high doses and side effects are typically only mild to moderate, transient, and CNS related. All AEDs can cause suicidal ideation or behavior, and patients taking AEDs should be monitored for this. In a well-controlled QT safety study, cardiac repolarization was not affected.
Teratogenicity
Teratogenicity data are not currently available as pregnant women and women who are nursing are excluded from participating in any of the clinical studies. During animal toxicity studies, brivaracetam doses up to 120 mg/kg/day were administered to rats and rabbits and failed to demonstrate any effect on fertility, pregnancy, or early embryonic development (15).
Special Safety Concerns
Serological or other special monitoring is not necessary for brivaracetam. Toxicity studies revealed no alteration in chemistry laboratory data despite high doses of brivaracetam. Carbamazepine’s 10,11 epoxide metabolite increases with addition of high-dose brivaracetam to carbamazepine, and if that occurs, carbamazepine levels as well as carbamazepine-induced side effects should be monitored.
Drug Interactions
Brivaracetam demonstrates few drug–drug interactions with other AEDs. At brivaracetam doses of greater than 50 mg/day, the 10, 11 active epoxide metabolite of carbamazepine increased, and at a dose of 100–150 mg/day, the carbamazepine epoxide metabolite approached the upper limit of normal. Enzyme-inducing AEDs resulted in a slightly increased brivaracetam clearance. Non-enzyme-inducing AEDs did not result in changes in plasma concentration of brivaracetam, and brivaracetam did not alter metabolism of other AEDs. The same is true for oral hormonal contraception, in that neither brivaracetam nor oral contraception resulted in alteration of metabolism of the other (15).
Use in Special Populations
Data on use of brivaracetam in pregnancy and while breast-feeding are not available. However, as mentioned previously, animal toxicology studies failed to reveal signs of abnormal fetal development, indicating that this medication may be safe in pregnancy. Age, gender, race, and renal function did not affect plasma brivaracetam levels. Plasma brivaracetam levels in elderly patients with severe renal impairment not requiring dialysis resembled those in nonelderly healthy patients. In patients with severe hepatic impairment, brivaracetam exposure increased by 50% to 60% compared to healthy controls and therefore use of this medication in that population should be limited or decreased (15).
Pediatric Use
Brivaracetam use in pediatrics is not presently recommended. Studies are underway investigating the dose and efficacy of this medication in children aged 1 month to 16 years with generalized or partial-onset epilepsy. The estimated efficacious dose in this age group is likely going to resemble the adult dose at approximately 1–5 mg/kg/day.
GANAXOLONE
Indications
Ganaxolone is the 3B methylated synthetic analog of allopregnanolone currently undergoing Phase II trials in anticipation of applying for FDA approval for adjunctive treatment of partial-onset epilepsy in adults and refractory infantile spasms in children. It is considered a neurosteroid and related to progesterone but is hormonally inactive.
Dosing
Dosing for ganaxolone is still under investigation. Clinical trials have investigated doses of 900 mg/day to 1,500 mg/day in adults. In children, doses of up to 54 mg/kg have been used. It is administered twice a day (2).
Pharmacology
Ganaxolone demonstrates two mechanisms of action depending on its concentration. At low doses, ganaxolone potentiates the action of gamma-aminobutyric acid (GABA) at GABAA receptors. With higher doses, it directly activates the GABAA receptors and prolongs opening of the Cl channel. Ganaxolone modulates both extrasynaptic and synaptic GABAA receptors. Activation of the extra synaptic receptors results in a persistent inhibition of neuronal excitability. Synaptic GABA receptor activation provides phasic inhibition (16). The extrasynaptic activity may be more important in cases of prolonged seizures and status epilepticus as synaptic GABA receptors may internalize with prolonged seizures, making them unavailable.
Ganaxolone is rapidly absorbed with Tmax occurring 1.5 to 2 hours after ingestion. After high fat or high carbohydrate meals, ganaxolone absorption is decreased slightly. It is widely distributed and highly protein bound. It is extensively metabolized to mostly unidentified compounds by the CYP3A4 system. Excretion occurs primarily via the fecal route and only 20% excretion occurs through the kidneys (17). The plasma half-life is approximately 20 hours and no sex differences exist for metabolism of the medication. The drug exhibits linear kinetics with direct correlation between dosage and plasma concentration levels. Steady-state concentrations are achieved within 48 hours of ingesting medication.
Efficacy Data
Efficacy of ganaxolone as adjunctive therapy in partial seizures in adults was evaluated in a Phase II study. A dose of 1,500 mg/day was compared to placebo. A significantly greater reduction of seizure frequency was noted with ganaxolone (18%) as compared to placebo (2%). In the open-label extension, over 90% of subjects continued participation and of those, the majority remained on the study drug throughout the entire 104-week period before tapering (2).
In the pediatric population, ganaxolone has been evaluated for treatment of infantile spasms. No significant different was noted between drug and placebo in the primary end point, spasm cluster frequency. However, 17% of patients had a marked or moderate improvement in spasms with ganaxolone compared to 0% for placebo (15). Further investigations are planned on pediatric patients with infantile spasms.
Efficacy in Other Conditions
Ganaxolone is currently being investigated as a migraine prophylaxis medication at doses of 750 mg/day. So far a significant therapeutic benefit has not been realized. Clinical trials using ganaxolone in mood disorders have been performed, but data are not yet available.
Adverse Effects
In adults, the most common adverse effects of ganaxolone were dizziness, somnolence, and diarrhea. Serious adverse events occurred with the same frequency in the active treatment arm compared to the placebo arm. Other side effects included headache, convulsions, fatigue, fall, nasopharyngitis, dizziness, contusion, and nasal congestion (2). Weight change was not noted and vital signs or ECG changes were not observed in the clinical trials.
In children, the most commonly observed adverse events were somnolence, diarrhea, nervousness, and vomiting. Of note, one of the more concerning side effects seen in children is agitation, although occasionally behavioral improvement may occur as well (17).
Toxicity, Overdose, and Contraindications
Toxicity studies on ganaxolone revealed the most common toxicity was dose-related, reversible sedation. With either single or multiple dosing of ganaxolone, target organ damage was not identified and hematologic and serum chemistries were not altered. Mutagenicity and carcinogenicity was not observed. In assessing CNS side effects in mice, ganaxolone had less interaction when coupled with alcohol than valproic acid did, and resulted in less cognitive impairment and ataxia. Maximum tolerated doses of ganaxolone in rodent studies were limited by sedation and/or liver weight gain associated with CYP induction. Continued toxicology studies reinforce the safety of ganaxolone with long term (15). Toxicology has not been determined in clinical studies.
Warning and Precautions
Currently, there are no serious warnings or precautions in adults for ganaxolone. In pediatrics, agitation is a concerning side effect seen, but there do not appear to be any predisposing factors demonstrating predictability.
Teratogenicity
Teratogenicity effects of ganaxolone in human are currently unavailable. In rats, however, up to 300 mg/kg/day failed to demonstrate any significant change in fetal development.
Special Safety Concerns
Based on available studies, no serological monitoring is recommended for ganaxolone. Ganaxolone did not demonstrate any changes in chemistry, hematology, vital signs, or physical and neurological examinations. ECGs remained stable throughout the treatment period.
Drug Interactions
Ganaxolone is extensively metabolized by the liver with at least some metabolism occurring via the CYP3A4 enzyme system. It is not an inducer or inhibitor of this enzyme system. However, in vitro studies demonstrated reduced plasma concentration with coadministration of strong CYP3A4 inducers such as carbamazepine and phenytoin. Conversely, strong CYP3A4 inhibitors result in significantly increased plasma concentrations of ganaxolone, as demonstrated in an in vitro study using ketoconazole (17). However, in clinical studies for adult and pediatric populations, no significant interactions were noted, including in subjects concomitantly taking ganaxolone and one of the afore-mentioned drugs. In addition, no protein-binding interactions were identified with coadministration of valproic acid and ganaxolone despite ganaxolone’s high level of protein binding.
Use in Special Populations
Although no teratogenicity has been demonstrated in rats, no clinical trials have investigated ganaxolone’s teratogenicity effects or its distribution in breast milk. Recommendations remain to avoid ganaxolone in pregnant women or women who are breastfeeding.
Only 20% of ganaxolone and its metabolites are excreted via the kidneys, and although there are no specific data addressing use of ganaxolone in renally impaired patients, it seems intuitive that at least mild-to-moderate renal impairment would not require dose adjustments. Alternatively, because of ganaxolone’s extensive first-pass metabolism in the liver, moderate-to-severe liver impairment may limit its use in these patients.
Pediatric Use
Ganaxolone is being evaluated for the treatment of refractory infantile spasms. Tolerated doses include up to 54 mg/kg/day, but with inconsistent results, as noted earlier. Additional studies are planned.
