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Pregabalin and Rufinamide

By Andrea Cheng-Hakimian, M.D., and Gail Anderson, PhD

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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-aminobutyric 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 an adjunctive treatment for partial seizures in adults. It is now commercially available as a Schedule IV controlled substance.

Pregabalin exhibits simple pharmacokinetics, with extensive, rapid bioavailability and no protein binding, and is largely excreted unchanged (see chart). Lower doses are needed in patients with decreased renal function (i.e., the 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 (placebo: 5%, 150 mg/d: 2%, 300 mg/d: 14%, 600 mg/d: 24%). As with gabapentin, myoclonus has been reported. Present in 4 out of 19 patients, myoclonus was most severe in the 600 mg/d group and subsided with reduction of dose.

Pregabalin is a newly available antiepileptic drug that is structurally and functionally similar to gabapentin. Its benefits include predictable and linear pharmacokinetics and few drug–drug interactions.
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, randomly assigned 453 subjects to five treatment groups (placebo, 50, 150, 300, or 600 mg/d of pregabalin, all administered twice daily). A dose-related reduction in seizure frequency was seen (placebo-7%, 50 mg/d-12%, 150 mg/d-34%, 300 mg/d-44%, 600 mg/d-54%). Arroyo et al., Epilepsia 2004, randomly assigned 287 subjects to take a 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, randomly assigned 312 subjects to take a placebo, 600 mg/d administered twice a day, or 600 mg/d administered three times a day. Seizure reduction of -1% for the placebo group, 44% for the twice a day group, and 53% for the three times a day group was reported.

In conclusion, pregabalin is a newly available antiepileptic drug that is structurally and functionally similar to gabapentin. Its benefits include predictable and linear pharmacokinetics and few drug-drug interactions. Efficacy and tolerability have 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 to the authors' knowledge, no adequate direct comparison of the efficacy of gabapentin and pregabalin has been performed.

Rufinamide


Rufinamide, trade name Banzel, 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 use of 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 and 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 increases the Cmax, so dosing with food should be considered. However, consistency is important, as the highest fluctuations in blood levels are seen if one dose is taken with food and another is taken in fasting state.

Adverse effects were reported as mild to moderate and did not lead to discontinuation. Effects included 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. Rufinamide did not in turn 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 in which 50 subjects were randomly assigned to a placebo or weekly ascending doses of rufinamide at 400, 800, 1200, 1600 mg/day administered twice daily. The seizure frequency ratio (seizures per 28 days in the treatment phase divided by those 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. In this study, 647 subjects were randomly assigned to take 200, 400, 800, 1600 mg/d of rufinamide or a placebo. The reported results were in favor of rufinamide, with p=0.003. Vasquez et al. (abstract, Epilepsia 2000) reported on 313 subjects randomly assigned to take a placebo or 3200 mg/d of rufinamide. A 20.4% reduction relative to baseline for rufinamide vs. a 1.6% median increase for placebo was noted.

Several clinical trials of rufinamide have shown efficacy for partial seizures in adults, pediatric patients, and patients with Lennox-Gastaut Syndrome.
Efficacy in the pediatric population has also been examined. An open-label trial by Litzinger et al. published 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 in Neurology 2005 (abstract). In 138 subjects aged 4-37 years randomly assigned to take 45 mg/kg/d of rufinamide or a placebo as add-on therapy, the median seizure reduction compared with baseline was 11.7% for the 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, pediatric patients, and patients with Lennox-Gastaut Syndrome. The FDA is evaluating the drug for the treatment of partial seizures in adults and patients with Lennox-Gastaut Syndrome.

Pregabalin and Rufinamide

 

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 Decreased estrogen levels

Others

EtOH/benzodiazepines No studies in literature
Dosing B.I.D. B.I.D.
Adverse Effects 10–35%, up to 20% discontinuation rate at highest doses 10–25%, rare discontinuation
appointment