Pharmacotherapy of epilepsy: newly approved and developmental agents.
This article discusses seven newly available antiepileptic drugs (AEDs) and agents in phase III development. Lacosamide, licensed as an adjunctive treatment for partial-onset seizures, primarily acts by enhancing sodium channel slow inactivation. At daily doses of 200-600 mg, the drug significantly reduced partial-onset seizures in adults with refractory epilepsy. The most common adverse effects are CNS related. Rufinamide, available as adjunctive treatment for seizures associated with Lennox-Gastaut syndrome, has an unclear mechanism of action, although it does block voltage-dependent sodium channels. Coadministration of valproic acid significantly increases rufinamide circulating concentrations. The drug has been shown to have efficacy for partial-onset, primary generalized tonic-clonic, tonic-atonic, absence and atypical absence seizures. Adverse effects are mainly somnolence, nausea and vomiting. Eslicarbazepine acetate, a carbamazepine analogue, was recently licensed as adjunctive treatment for partial-onset seizures. Eslicarbazepine acetate acts at voltage-gated sodium channels, although the precise mechanism of action is unclear. The drug had efficacy for partial-onset seizures in three randomized, double-blind, placebo-controlled studies, using 400, 800 or 1200 mg/day. Adverse effects include dizziness and somnolence. Retigabine (ezogabine) exerts its anticonvulsant effect through the opening of neuronal voltage-gated potassium channels. Following significant seizure reduction rates at dosages of 600, 900 and 1200 mg/day, license applications have been submitted for its use as adjunctive treatment for patients with partial-onset seizures. Dose-related adverse effects include somnolence, confusion and dizziness. Brivaracetam is the n-propyl analogue of levetiracetam. Mixed results have been obtained in phase III studies in patients with partial-onset seizures, and further trials in children, patients with photosensitive epilepsy and patients with partial-onset seizures are ongoing. Dizziness, headache and somnolence are the most common adverse effects reported. Perampanel was designed as an AMPA-type glutamate receptor antagonist. Following encouraging results from phase II studies in patients with refractory partial-onset seizures, recruitment for phase III trials is almost complete. Ganaxolone is a neurosteroid with potent antiepileptic activity that modulates GABA(A) receptors in the CNS. Ganaxolone has shown promise in a variety of seizure types. Dizziness and somnolence have been reported in some patients. The availability of new AEDs has widened the choices for clinicians treating patients with epilepsy. However, given the minimal improvement in prognosis and disappointing efficacy outcomes in double-blind, placebo-controlled, dose-ranging regulatory trials, it seems unlikely that these novel agents will have a major impact on outcomes for people with epilepsy.
Epilepsy Unit, Division of Cardiovascular and Medical Sciences, Western Infirmary, Glasgow, Scotland.
Linda J
LJ
Stephen
Martin J
MJ
Brodie
D000818:Animals; D000927:Anticonvulsants / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D002986:Clinical Trials as Topic; D004347:Drug Interactions; D004827:Epilepsy / Q000188:drug therapy*; D006801:Humans
D000927:Anticonvulsants
Epilepsia. 2007 Jul;48(7):1303-7
17521343
Nat Rev Neurosci. 2005 Nov;6(11):850-62
16261179
Epilepsia. 2010 Jan;51(1):7-26
19744114
Neurology. 2010 Nov 16;75(20):1817-24
20944074
Eur J Clin Pharmacol. 2003 Apr;58(12):795-802
12698305
J Clin Pharmacol. 2002 Feb;42(2):175-82
11831540
Epilepsy Behav. 2010 Jul;18(3):322-4
20570216
Neurology. 2007 Apr 10;68(15):1197-204
17420403
J Pharmacol Exp Ther. 1997 Aug;282(2):543-53
9262314
Cochrane Database Syst Rev. 2009 Jul 08;(3):CD003277
19588340
Epilepsia. 2007 Mar;48(3):497-504
17319919
Neurosci Lett. 1995 Aug 4;195(2):77-80
7478272
Epilepsia. 2001 May;42(5):600-8
11380566
Clin Pharmacol Ther. 2003 Jan;73(1):61-70
12545144
Adv Exp Med Biol. 2004;548:34-56
15250584
J Neurosci. 2005 May 18;25(20):5051-60
15901787
Epilepsia. 2006 Nov;47(11):1803-9
17116018
Drug Metab Dispos. 1999 May;27(5):613-22
10220491
Epilepsy Res. 2006 Jun;69(3):273-94
16621450
Epilepsia. 2008 Jul;49(7):1213-20
18325020
Epilepsia. 2008 Jul;49(7):1123-41
18503564
Seizure. 2009 Jul;18(6):453-6
19211275
Nat Genet. 1998 Jan;18(1):53-5
9425900
Trends Neurosci. 2000 Sep;23(9):393-8
10941184
J Pharmacol Exp Ther. 1998 Mar;284(3):868-77
9495844
Drugs Today (Barc). 2008 Jul;44(7):531-45
18806903
Curr Med Res Opin. 2010 Jun;26(6):1355-62
20377319
Epilepsia. 2007 Jul;48(7):1308-17
17635557
Expert Rev Neurother. 2006 Mar;6(3):397-406
16533143
Neurology. 1993 Nov;43(11):2284-91
8232944
Drug Metab Dispos. 2008 Jan;36(1):36-45
17908923
Mol Pharmacol. 2009 Feb;75(2):272-80
19015229
Epilepsia. 2009 Aug;50(8):1899-909
19490053
Neurology. 2008 May 20;70(21):1950-8
18401024
CNS Drugs. 2009;23(1):71-9
19062776
Epilepsy Res. 2009 Jul;85(1):1-30
19406620
Neurotherapeutics. 2007 Jan;4(1):18-61
17199015
Epilepsia. 2006 Jul;47(7):1153-9
16886978
Acta Neurol Scand. 2009 Nov;120(5):281-7
19832771
Neurotherapeutics. 2007 Jan;4(1):84-7
17199019
Br J Clin Pharmacol. 2008 Jul;66(1):71-5
18341673
Adv Neurol. 1999;79:947-63
10514878
J Med Chem. 1999 Jul 15;42(14):2582-7
10411478
Drugs. 2009;69(4):449-59
19323588
Eur J Pharmacol. 2003 Jan 24;460(2-3):109-16
12559370
Mayo Clin Proc. 1996 Jun;71(6):576-86
8642887
Pharmacol Rep. 2009 Mar-Apr;61(2):197-216
19443931
Epilepsia. 1997 Sep;38(9):1026-31
9579942
Br J Clin Pharmacol. 2003 Jul;56(1):39-45
12848774
Neurology. 2009 Feb 3;72(5):439-46
19188575
Epilepsia. 2010 Oct;51(10):1963-9
20662896
Neurochem Int. 2002 Apr;40(5):435-40
11821151
Neurosci Lett. 2000 Mar 17;282(1-2):73-6
10713399
Epilepsia. 2009 Mar;50(3):443-53
19183227
Pain. 2008 Sep 15;138(3):537-545
18331780
Epilepsy Res. 2001 Jan;43(1):11-58
11137386
Ann Neurol. 2007 Oct;62(4):375-81
17253624
Mol Pharmacol. 2008 Jan;73(1):157-69
17940193
J Pharmacol Exp Ther. 1957 Mar;119(3):299-309
13417082
Xenobiotica. 1997 May;27(5):431-41
9179986
Eur J Pharmacol. 1996 May 15;303(3):163-9
8813562
Epilepsy Res. 2004 Sep-Oct;61(1-3):1-48
15570674
Mol Pharmacol. 2005 Apr;67(4):1009-17
15662042
Neurology. 2010 Aug 10;75(6):519-25
20592253
Neurotherapeutics. 2007 Jan;4(1):88-96
17199020
Epilepsy Res. 2001 May;44(2-3):197-206
11325575
Epilepsia. 2008 Mar;49(3):418-24
17888078
J Pain. 2009 Aug;10(8):818-28
19409861
Epilepsy Res. 2000 Dec;42(2-3):133-9
11074186
Neurotherapeutics. 2007 Jan;4(1):102-5
17199022
IDrugs. 2003 May;6(5):479-85
12789603
Epilepsia. 2000 Aug;41(8):1068-9
10961644
J Med Chem. 2004 Jan 29;47(3):530-49
14736235
Expert Opin Emerg Drugs. 2007 Sep;12(3):407-22
17874969
Epilepsy Res. 2009 Jan;83(1):1-43
19008076
Epilepsia. 2009 Mar;50(3):454-63
19243424
CNS Drug Rev. 2007 Spring;13(1):21-42
17461888
J Pharmacol Exp Ther. 2009 Mar;328(3):951-62
19098162
Mol Neurobiol. 2003 Aug;28(1):51-64
14514985
Nat Rev Drug Discov. 2010 Jan;9(1):68-82
20043029
Science. 1998 Jan 16;279(5349):403-6
9430594
Crit Rev Neurobiol. 1995;9(2-3):207-27
8581984
Am Heart J. 1991 May;121(5):1421-9
2017974
Br J Clin Pharmacol. 2007 Jun;63(6):680-8
17223857
Epilepsy Behav. 2009 Mar;14(3):491-5
19162229
Neuropharmacology. 2001;40(1):28-35
11077068
J Pharmacol Exp Ther. 2005 Jul;314(1):282-92
15814569
Epilepsy Res. 2010 Feb;88(2-3):255-63
20061123
J Physiol. 2008 Apr 1;586(7):1791-801
18238816
Epilepsia. 2010 Jun;51(6):958-67
20132285
Epilepsia. 2010 Jun;51(6):1069-77
19889013
Clin J Pain. 2009 Jun;25(5):376-85
19454870
J Pharmacol Exp Ther. 1997 Mar;280(3):1284-95
9067315
Neurology. 2009 Feb 17;72(7):664-9
19221301
Epilepsia. 2000 Sep;41(9):1187-94
10999558
Rev Med Interne. 2008 Feb;29(2):152-4
17976866
Epilepsy Res. 1999 Mar;34(1):1-41
10194110
Epilepsy Res. 2007 Jan;73(1):1-52
17158031
Mol Neurobiol. 2006 Feb;33(1):17-32
16388108
Epilepsy Behav. 2008 Jan;12(1):49-53
18086455
Eur J Clin Pharmacol. 2008 Mar;64(3):267-73
18157705
Cardiovasc Drugs Ther. 1995 Oct;9(5):709-14
8573554
Neurology. 2008 Jan 1;70(1):54-65
18166707
J Neurosci. 2001 Aug 1;21(15):5535-45
11466425
Epilepsia. 2007 Oct;48(10):1870-4
17634060
Int J Neuropsychopharmacol. 2006 Apr;9(2):191-200
16174428
Ann Neurol. 2007 Oct;62(4):382-9
17880009
Neurology. 2007 Sep 4;69(10):1027-34
17785672
Br J Pharmacol. 2008 Aug;154(8):1662-71
18500360
Neurotherapeutics. 2007 Jan;4(1):155-62
17199032
Epilepsy Res. 2001 Feb;43(2):115-24
11164700
Epilepsy Res. 2005 Oct-Nov;67(1-2):81-7
16214306
Nat Genet. 1998 Jan;18(1):25-9
9425895
Int J Clin Pharmacol Ther. 2008 Mar;46(3):119-30
18397682
Epilepsy Res. 1996 Apr;23(3):211-23
8739124
Neurology. 2008 Jul 15;71(3):177-83
18625963