Use of the New Antiepileptic Agents

1. Use of the New Antiepileptic Agents Anthony Murro, M.D.

2. Research Support • I currently received support for research involving biravacetam from UCB

3. New Antiepileptic Agents • Lacosamide (Vimpat) • Rufinamide (Banzel) • Vigabatrin (Sabril) • Clobazam (Onfi) • Ezogabine (Potiga)

4. Lacosamide • Adjunctive therapy in the treatment of partial-onset seizures • Functionalized amino acid

5. Lacosamide - Mechanism • Lacosamide facilitates slow inactivation of voltage gated sodium ion channels

6. Lacosamide - Slow inactivation • Membrane depolarization occurs • A relatively slower & more sustained ion channel conformation occurs at a intra-membrane channel site • This conformation blocks sodium ion flow • Lacosamide enhances slow inactivation • (Goldin, 2011)

7. Sodium Ion Channel Fast Inactivation • Voltage gated sodium ion channel conformation occurs post-depolarization • An intracellular protein segment (inactivating particle) binds to a docking site & blocks sodium ion flow • Carbamazepine, felbamate, lamotrigine, phenytoin, oxcarbazepine, topiramate enhance fast inactivation • (Goldin, 2011)

8. Slow inactivation Intra-membrane sites S5 & S6 block ion channel

9. Fast Inactivation Intracellular loop between domains III & IV blocks ion channel

10. CRMP-2 Binding • Lacosamide also binds to a collapsin response mediator protein-2 (CRMP-2)

11. CRMP-2 Binding • This protein performs important roles that include cytoskeletal, vesicle, and synaptic functions in the developing brain. • The significance of this binding is an area of current research (Hensley et al., 2011)

12. Lacosamide Dosing • Adult: 50 mg twice daily; may be increased at weekly intervals by 100 mg/day • Maintenance dose: 200-400 mg/day

13. Lacosamide Metabolism • Linear kinetics 100-800 mg/d dose • Metabolism (CYP2C19) by de-methylation to form O-desmethyl-lacosamide (inactive) • No significant induction/inhibition or P450 mediated interaction (Chu et al, 2010)

14. Lacosamide Effectiveness • Multi-center randomized prospective controlled trials • > 400 patients per trial • Age 16 years and older • Adjunctive therapy with 1-3 anti-epileptic medications

15. Lacosamide Median Sz Reduction Group Ben-Menachem Halasz Placebo 10% 20.5% 200 mg/d 26% 35.3% 400 mg/d 39% 36.4% 600 mg/d 40% --- (Ben-Menachem et al, 2007, Halasz et al, 2009)

16. Lacosamide Effectiveness • Dose of 600 mg/day not more effective but did have increased side effect risk • Events leading to discontinuation: Dizziness, nausea, ataxia, vomiting, nystagmus • (Ben-Menachem et al, 2007)

17. Effect of Sodium Channel Blocker Retrospective analysis suggests: • Lacosamide will reduce seizure frequency even when combined with a fast sodium channel blocker (Sake et al., 2010, Stephen et al., 2011)

18. Effect of Sodium Channel Blocker Retrospective analysis suggests: • Lacosamide with a sodium channel blocker (e.g. phenytoin) will lead to less seizure reduction & increased side effects • Caution: Post-hoc analysis, small samples, multiple comparisons, and potential confounding factors. (Sake et al., 2010, Stephen et al., 2011)

19. Lacosamide Pooled Analysis Median Seizure Reduction Sodium Channel Blocker GroupPresentAbsent Placebo 18.9% 28% 200 mg/d 33.3% 38% 400 mg/d 39% 62.5% 600 mg/d 42.7% 79%

20. Lacosamide Case Reports • Intravenous lacosamide has been used to treat status epilepticus & seizure clusters. Bolus of 200 mg IV at rate of 60 mg/min (Höfler et al., 2011) • Lacosamide has been used in primary generalized epilepsy (Afra et al., 2012) • A single report described worsening of seizures in Lennox Gastaut syndrome with lacosamide (Cuzzola et al., 2010)

21. Lacosamide Summary Positive • No significant drug interactions • Common side effects are dose dependent & easily managed with dose reduction • Infrequent need for serum drug levels • Low protein binding Negative • High cost

22. Role of Lacosamide • The favorable profile makes lacosamide a likely early choice for adjuvant drug therapy of partial seizures • Future research might confirm effectiveness for primary generalized epilepsy & status epilepticus. • Future research might confirm greater benefit among patients not using sodium channel blockers

23. Rufinamide • Adjunctive therapy in the treatment of generalized seizures of Lennox-Gastaut syndrome (LGS)

24. Rufinamide Mechanism • Rufinamide slows sodium ion channel recovery from the inactivated state & limits repetitive neuronal firing

25. Rufinamide Dosing • Children: Initial: 10 mg/kg/day in 2 equally divided doses; increase dose by ~10 mg/kg every other day to a target dose of 45 mg/kg/day or 3200 mg/day (whichever is lower) in 2 equally divided doses • Adults: Initial: 400-800 mg/day in 2 equally divided doses; increase dose by 400-800 mg/day every other day to a maximum dose of 3200 mg/day in 2 equally divided doses.

26. Rufinamide Oral Absorption • Oral absorption increases with food due to increased solubility (33% increase overall absorption & 50% increase in peak concentration). • Keep relationship with meals constant.

27. Rufinamide Metabolism • Carboxylesterase metabolism to inactive metabolite • Rufinamide is a weak CYP3A4 inducer • Non-linear drug kinetics

28. Rufinamide Drug Levels • Drug levels correlate with effectiveness and frequency of adverse effects • Mean plasma level causing a 50% decrease of seizure frequency was 30 mg/l; range in studies: 5-55 mg/l.

29. Rufinamide Drug Interactions • Mild increased clearance of oral contraceptives (CYP3A4 induction) • Phenobarbital, primidone, phenytoin, carbamazepine induce carboxyesterase & significantly increase rufinamide clearance • Valproate significantly increases rufinamide levels by 60-70%

30. Rufinamide Lennox Gastaut Median Seizure Reduction GroupAll SeizuresTonic-atonic Placebo 11.7% -1.4% 45 mg/kg-d 32.7% 42.5% (Glauser et al., 2007)

31. Rufinamide Partial Seizures Median Seizure Reduction GroupSeizure Reduction Placebo -1.6% Rufinamide* 20.4% Dose: 1200-3200 mg/d (mean 2800 mg/d) (Brodie et al, 2007)

32. Adverse Effects • Most common: Dizziness, fatigue, somnolence, nausea, headache • AED hypersensitivity syndrome (rash & fever) has occurred 1-4 weeks after therapy & more likely in children • No significant effects on working memory, psychomotor speed, or attention • (Wheles et al. 2010)

33. Rufinamide QT shortening • > 20 msec reduction in QT can occur but in in study population had < 300 msec • Rufinamide should not be given to those with familial short QT syndrome potassium channelopathy • Do not administer in situations with reduced QT interval: digoxin, hpercalcemia, hyperkalemia, acidosis

34. Myoclonic-astatic epilepsy (Doose syndrome) • Onset age 1-6 years of age • Myoclonic, astatic, & myoclonic-astatic Sz • Normal development prior to seizures • Prognosis variable: spontaneous resolution in some; prolonged non-convulsive status epilepticus, cognitive impairments & evolution to Lennox-Gastaut in others • EEG: 2-3 Hz generalized spike wave • MRI normal

35. Myoclonic-astatic epilepsy & Rufinamide • In a case series, rufinamide adjunctive therapy reduced seizure frequency by >75% in 6 of 7 cases • Seizure reduction decreased for patients followed over longer time intervals of 6-18 months (von Stülpnagela et al. 2012)

36. Rufinamide Summary Positive • Most side effects are dose dependent & easily managed with dose reduction • Infrequent need for serum drug levels • Low protein binding Negative • Significant drug interactions are possible • High cost

37. Role of Rufinamide • Rufinamide has features similar to many of the approved drugs for Lennox-Gastaut (e.g. lamotrigine, topiramate). • Future research might confirm the beneficial effect of rufinamide for treatment of myoclonic-astatic epilepsy.

38. Vigabatrin • Adjunctive treatment for infantile spasms and adult refractory complex partial seizure

39. Vigabatrin Mechanism • Irreversible & competitive binding to GABA transaminase (Chu-Shore et al., 2010)

40. Vigabatrin Mechanism • Possibly also might stimulate GABA release • Brain GABA increases by 40% at 2 hours post-dose • (Chu-Shore et al., 2010)

41. Vigabatrin • Linear dose relationship • Reduces phenytoin level by 20% • Dosage adjustment for decreased renal clearance • (Chu-Shore et al., 2010)

42. Vigabatrin Dosing Complex Partial Seizures • Adults: Initial: 500 mg twice daily; increase daily dose by 500 mg at weekly intervals based on response and tolerability. Recommended dose: 3 g/day • Children: Oral: Initial: 40 mg/kg/day divided twice daily; maintenance dosages based on patient weight

43. Vigabatrin Dosing Infantile Spasm • Initial dosing: 50 mg/kg/day divided twice daily; may titrate upwards by 25-50 mg/kg/day every 3 days to a maximum of 150 mg/kg/day

44. Vigabatrin Effectiveness Complex Partial Seizures (Dean et al., 1999)

45. Vigabatrin Effectiveness Complex Partial Seizures (French et al., 1996)

46. Vigabatrin Treats Infantile SpasmsTuberous Sclerosis Responds Best Group% Spasm Free day 14 Vigabatrin low dose 11% Vigabatrin high dose 36% • Tuberous sclerosis 52% • Cryptogenic 27% • Symptomatic 10% Low: 18-36 mg/kg-d; High: 100-148 mg/kg-d (Elterman et al., 2001)

47. Hormonal Therapy Better Early Response For Non-Tuberous Sclerosis Cases Percent Spasm Free Group2 wks*12-14 months Hormonal 73% 75% Vigabatrin 54% 76% • Significant difference (Lux et al., 2005) Tuberous sclerosis cases were excluded

48. Better Cognitive Outcome: Hormonal Treatment Cryptogenic Cases Outcome at 12-14 months Following Treatment SymptomaticVineland Adaptive Behavior Scale Hormonal 70.8 Vigabatrin 75.9 Cryptogenic*Vineland Adaptive Behavior Scale Hormonal 88.2** Vigabatrin 78.9** • Significant difference (Lux et al., 2005) Tuberous sclerosis cases were excluded

49. Better Cognitive Outcome: Hormonal Treatment Cryptogenic Cases Outcome at 4 years Following Treatment SymptomaticVineland Adaptive Behavior Scale Hormonal 45 Vigabatrin 50 Cryptogenic*Vineland Adaptive Behavior Scale Hormonal 96 Vigabatrin 63 * Significant difference (Darke et al., 2005) Tuberous sclerosis cases were excluded

50. Vigabatrin Effectively Treats Tuberous Sclerosis Practice Parameter: Medical Treatment of Infantile Spasms: “Overall cessation of spasms was seen in 41 of 45 (91%) of children treated with vigabatrin, with a 100% response rate seen in five studies.” (Mackay et al. 2004)