University of Washington Regional Epilepsy Center at Harborview Medical Center

New Antiepileptic Drugs

by Andrea Cheng Hakimian, M.D. and Gail Anderson, Ph.D.

Pregabalin

Pregabalin, trade name Lyrica , is a new antiepileptic drug developed by Pfizer. Similar structurally and mechanistically to gabapentin, it is a 3-substituted analogue of gamma-amino butyric acid (GABA). Pregabalin is thought to bind to the alpha2-delta subunit of voltage gated calcium channels in the CNS, attenuating calcium influx induced by depolarization at nerve terminals and reducing glutamate, noradrenalin, and substance P release. In June 2005, pregabalin received FDA approval as adjunctive treatment of partial seizures in adults. It is now commercially available as a Schedule IV controlled substance.

Pregabalin exhibits simple pharmacokinetics, with extensive, rapid bioavailability, no protein binding, and is largely excreted unchanged (see chart). Lower doses are needed in patients with decreased renal function (i.e., elderly). Steady state is achieved within 24-48 hours of repeated administration. No drug-drug interactions were found in a study with carbamazepine, phenytoin, lamotrigine, and valproate. Its sedative effects are additive with oxycodone, and may potentiate the effects of EtOH and benzodiazepines.

Adverse effects are dose dependent. Most frequent are dizziness (placebo-9%, 600 mg/d-43%), somnolence (placebo-11%, 600mg/d-28%), and ataxia (placebo-3%, 600 mg/d-15%). Blurred vision, tremor, incoordination, and dry mouth are also reported (5-10% above placebo). Weight gain is reported in 12.4% (placebo-0.5kg, 600 mg/d- 2.3kg). Withdrawal rates show clear dose dependence (5.0% - placebo, 1.2% - 150 mg/d, 14% - 300 mg/d, and 24% - 600 mg/d group). As with gabapentin, myoclonus has been reported. Present in 4/19 patients, myoclonus was most severe in the 600 mg/d group, and subsided with reduction of dose.

Three well-conducted, multicenter, randomized, double blind, placebo controlled trials established clinical efficacy in adults. Subjects had refractory partial seizures, and were followed by an eight-week baseline period before entering randomization. French et al, Neurology 2003, randomized 453 subjects to pregabalin at 50, 150, 300, and 600 mg/d divided bid. A dose-related reduction in seizure frequency was seen (placebo-7%, 50 mg-12%, 150 mg-34%, 300 mg-44%, 600 mg-54%). Arroyo et al, Epilepsia 2004, randomized 287 subjects to placebo, 150 mg/d, or 600 mg/d. Seizure reductions of -1.8% for placebo, 21% for 150 mg, and 48% for 600 mg were seen. Beydoun et al, Neurology 2005, randomized 312 subjects to placebo, 600 mg/d divided bid, or 600 mg/d divided tid. Seizure reduction of -1% for the placebo group, 44% for the bid group, and 53% for the tid group, was reported.

In conclusion, pregabalin is a newly available antiepileptic drug that is structurally and functionally similar to gabapentin. Its appeal includes predictable and linear pharmacokinetics, and few drug-drug interactions. Efficacy and tolerability has been established in three well-conducted clinical trials of partial epilepsy in adults. Pregabalin's higher potency in animal models suggests that efficacy should be achieved at lower doses. Since the efficacy of gabapentin may be limited by saturable absorption at higher doses, a higher potency of pregabalin may well prove to be an advantage in clinical practice, but no adequate direct comparison of the efficacy of gabapentin and pregabalin has been performed to the authors' knowledge.

Rufinamide

Rufinamide, trade name Inovelon , is a novel antiepileptic drug discovered by Novartis Pharmaceutical and acquired by Eisai Co. Orphan drug status for Lennox-Gastaut Syndrome was obtained from the FDA in October, 2004. An NDA has been submitted to the FDA for the drug as adjunctive therapy in adults and adolescents with partial onset seizures with and without secondary generalization. Rufinamide is a triazole derivative that exerts its effect by limitation of sodium dependent action potentials.

Rufinamide has good bioavailability, moderate protein binding, and is extensively metabolized with less than 2% excreted unchanged in the urine. Neither age nor sex alters pharmacokinetics. Administration with food increases absorption, decreases the Tmax, and increasing Cmax, so dosing with food should be considered. However, consistency is probably most important, as the highest fluctuations in blood levels are seen if one dose given with food and another in fasting state.

Adverse effects were described as mild to moderate and did not lead to discontinuation. These include fatigue (20%, placebo-4%), somnolence (24%, placebo-13%), tremor (12%, placebo-0), dizziness (8%, placebo 0), and vomiting (22%, placebo-6%), headache (varies from below placebo to up to 8% above placebo), diplopia (frequency not reported), and diarrhea (frequency not reported). No consistent effect on laboratory parameters, including EKG, was found.

Drug-drug interactions have been seen. Valproate increased trough rufinamide concentrations and decreased clearance by 25%. Phenobarbital, phenytoin, and primidone also increased rufinamide clearance by 25%. Carbamazepine, vigabatrin, oxcarbamazepine, and clobazam did not alter the pharmacokinetics of rufinamide. In turn, rufinamide did not alter trough concentrations of phenytoin, carbamazepine, valproate, phenobarbital, primidone, oxcarbamazepine, clonazepam, and clobazam.

Efficacy against refractory, adult-onset partial seizures was examined in three randomized placebo controlled trials. Palhagen et al, Epilepsy Research 2001, reported a study randomizing 50 subjects to placebo or weekly ascending doses of rufinamide at 400, 800, 1200, 1600 mg/day divided bid. The seizure frequency ratio (seizures per 28 days in treatment phase divided by that in the baseline phase) was lower in the rufinamide arm (0.59 vs. 1.52, p=0.04). Another, otherwise unpublished, study was reviewed by Bialer et al in Epilepsy Research, 1999. 647 subjects were randomized to 200, 400, 800, 1600 mg/d rufinamide vs placebo. Results were reported as in favor of rufinamide, with p=0.003. Vasquez et al (abstract, Epilepsia, 2000) reported on 313 subjects randomized to placebo or 3200 mg/d of rufinamide. A 20.4% reduction relative to baseline for rufinamide vs. 1.6% median increase for placebo was noted.

Efficacy in the pediatric population has also been examined. An open-label trial by Litzinger et al in Epilepsia, 1999 reported a 50% decrease in seizure frequency from baseline in four out of nine children. Glaser et al reported a randomized, controlled trial of subjects with Lennox-Gastaut Syndrome Neurology, 2005 (abstract). In 138 subjects aged 4-37 years randomized to 45 mg/kg/d of rufinamide or placebo as add-on therapy, the median seizure reduction compared with baseline was 11.7% for placebo and 32.7% for rufinamide (p=0.0001). The atonic-tonic seizure responder rate was also significant.

In conclusion, rufinamide has a novel mechanism of action. Early studies suggest better absorption when taken with food. Drug-drug interactions are present but not extensive. Several clinical trials have shown efficacy for partial seizures in adults, as well as the pediatric population and patients with Lennox-Gastaut Syndrome. The FDA is evaluating the drug for partial seizures in adults and the Lennox-Gastaut Syndrome.

	Pregabalin	Rufinamide
Bioavailability	> = 90%	Fed - 70%, Fasted - 49%
Protein binding	None	34%
Tmax	1h	Fed - 6h, Fasted - 8h
T ½	6h	Fed or fasted - 8-12h
Excretion	Renal	Hepatic
Hepatic enzyme induction or inhibition?	No	No
Hepatic metabolism?	No, drug excreted largely unchanged	Non-CYP450
Drug-drug interactions
AEDs	None to date	VPA, CBZ, PHT, PB, PM
OCPs	No	Decr. Estrogen levels
Others	EtOH/benzodiazepines	No studies in literature
Dosing	BID	BID
Adverse Effects	10-35%, up to 20% discontinuation rate at highest doses.	10-25%, rare discontinuation