IN THE 21 ST CENTURY Professor Martin J Brodie University of Glasgow Glasgow, Scotland
Eisai SODIUM CHANNEL BLOCKERS Declaration of interests UCB Pharma GlaxoSmithKline Lundbeck Takeda Advisory board, speakers bureau Advisory board, speakers bureau Advisory board, speakers bureau Advisory board, speakers bureau Advisory board GW Pharmaceuticals Advisory board Bial Newbridge Sanofi Aventis Abbott Advisory board Speakers bureau Speakers bureau Speakers bureau
Year of availability in the UK Phenytoin 1936 Carbamazepine 1965 Lamotrigine 1991 Oxcarbazepine 2000 Rufinamide 2007 Lacosamide 2008 Eslicarbazepine acetate 2009 Brodie MJ. CNS Drugs 2017; 31: 135-47
Differential effects on sodium channels Fast-inactivation state phenytoin, carbamazepine, oxcarbazepine Fast-inactivation state + others lamotrigine, rufinamide, Slow-inactivation state lacosamide, eslicarbazepine acetate Brodie MJ et al. Epilepsy & Behavior 2011; 21: 331-41
Range of efficacy All effective for focal and generalised tonic-clonic seizures BUT Lamotrigine has efficacy for absences, JME and Lennox-Gastaut syndrome AND Rufinamide is licensed as adjunctive treatment for Lennox-Gastaut syndrome PHENYTOIN, CARBAMAZEPINE AND OXCARBAZEPINE MAY EXACERBATE GENERALISED ABSENCES AND MYOCLONIC JERKS, A SCENARIO WHICH IS LESS APPARENT WITH LACOSAMIDE AND ESLICARBAZEPINE ACETATE Perucca E, Tomson T. Lancet Neurology 2011; 10: 446-56 Brodie MJ. Expert Review of Neurotherapeutics 2016; 16: 681-8
Shared side effects Dizziness Fatigue Diplopia Nausea Vomiting Drowsiness Ataxia ALL ARE DOSE-RELATED Brodie MJ. CNS Drugs 2017; 31: 135-47
Aplastic anaemia
Hepatotoxicity
Severe idiosyncratic reactions Stevens-Johnson syndrome Toxic epidermal necrolysis Hepatotoxicity Blood dyscrasias *DRESS syndrome Lupus-like syndrome *Drug Reactions with Eosinophila and Systemic Symptoms Brodie MJ et al. CNS Drugs 2017; 31: 135-47
Risk of dose-related teratogenicity Phenytoin 2.9 to 6.7% Carbamazepine 2.6 to 5.6% Lamotrigine 1.9 to 4.4% Oxcarbazepine 1.8 to 3.7% Rufinamide Lacosamide Eslicarbazepine acetate Unknown Unknown Unknown Tomson et al. Epilepsia 2015; 5: 1006-19
Phenytoin Phenytoin (diphenylhydantoin) was first synthesized by a German physician named Heinrich Biltz in 1908. Biltz sold his discovery to Parke-Davis, who did not find an immediate use for it
H Houston Merritt Tracy J Putnam (1902-1979) (1894-1975) Merritt HH, Putnam TJ. Sodium diphenylhydantoinate in the treatment of convulsive disorders. JAMA 1938;111:1068-75 Merritt HH, Putnam TJ. A new series of anticonvulsant drugs tested by experiments in animals. Arch Neurol Psychiat 1938;39: 1003-15
Phenytoin Quest: Find a less sedative antiepileptic drug than phenobarbital Method: Screen phenyl compounds against the convulsive threshold in cats Result: Several hundred chemicals were inactive except for Parke Davis s diphenylhydantoin Experiment: First treated patient became permanently seizure free after suffering daily episodes for many years. the rest is history!
Phenytoin GINGIVAL HYPERPLASIA
Phenytoin Saturation kinetics Gum hyperplasia, acne Facial coarsening, hirsutism Idiosyncratic reactions Frozen shoulder, Dupytren s contracture Cerebellar atrophy, peripheral neuropathy Dose-related teratogenicity Enzyme induction PROBLEMS ASSOCIATED WITH ITS USE Brodie MJ. CNS Drugs 2017; 31: 135-47
Carbamazepine Carbamazepine was synthesised by Schindler at Geigy in 1953 when the company was investigating tricyclic analogues of the recently introduced chlorpromazine
Carbamazepine Idiosyncratic reactions Hyponatraemia Dose-related teratogenicity Enzyme induction Autoinduction of metabolism PROBLEMS ASSOCIATED WITH ITS USE Brodie MJ. CNS Drugs 2017; 31: 135-47
CARBAMAZEPINE Serious allergic rashes HLA B*1502 x 2504 Asians HLA A*3101 x 26 Europeans Stevens-Johnson syndrome Chen P et al. New Engl J Med 2011; 364: 1126-33 McCormack M et al. New Engl J Med 2011; 364: 1134-43
Brodie MJ et al. Epilepsia 2013; 54: 11-27
ENZYME INDUCTION Targets Fifteen cytochrome P450 isoenzymes divided into 3 families involved in oxidative metabolism Two families of uridine-5 1 -diphosphoglutamyltransferases involved in glucuronidation ENZYMES LOCATED ON ENDOPLASTIC RETICULUM AND MITOCHONDRIAL MEMBRANES INSIDE CELLS Nebert DW, Russell DW. Lancet 2002; 360: 1155-62 Bock KW. Biochem Pharmacol 2010; 80: 771-7
ENZYME INDUCTION Cytochrome P450 targets Phenytoin 1A2, 2B6, 2C9, 2C19, 3A4/5 Carbamazepine 1A2, 2B6, 2C9, 2C19, 3A4/5 Phenobarbital 1A2, 2B6, 2C9, 3A4/5 Topiramate 3A4/5 Oxcarbazepine 3A4/5 Eslicarbazepine acetate 3A4 Brodie MJ et al. Epilepsia 2013; 54: 11-27
ENZYME INDUCTION Consequences Enzyme inducers accelerate the clearance of : many lipid soluble drugs eg oral contraceptives, warfarin, cytotoxics, antiretrovirals, statins, immunosuppressants other antiepileptic drugs eg phenytoin, carbamazepine, valproate, ethosuximide, lamotrigine, topiramate, tiagabine, zonisamide Brodie MJ et al. Epilepsia 2013; 54: 11-27
ENZYME INDUCTION Potential problems Unwanted pregnancy Increased cancer mortality Progressive AIDS Transplant rejection Uncontrolled hypertension Breakthrough pain etc, etc Brodie MJ et al. Epilepsia 2013; 54: 11-27
ENZYME INDUCTION Endogenous substrates Osteomalacia/osteoporosis Sexual dysfunction Increased vascular risk Gaitatzis A et al. Epilepsia 2012; 53: 1282-93 Brodie MJ et al. Epilepsia 2013; 54: 11-27 Chen Z et al. Neurology 2016; 87: 718-25
ENZYME INDUCTION Effects of antiepileptic drugs on lipids (n=5053) Mean non-high-density lipoprotein cholesterol in epilepsy patients taking enzyme inducers was 138mg/dl compared with 130mg/dl in non-inducers Patients on CBZ had a higher level of non-high-density lipoprotein cholesterol than those established on PB or PHT Yamamoto Y et al. Epilepsy Research 2016; 12: 101-6
Lamotrigine
Lamotrigine Slow titration schedule Allergic skin rashes Idiosyncratic reaction Occasional insomnia Contraception and pregnancy Dose-related teratogenicity PROBLEMS ASSOCIATED WITH ITS USE Brodie MJ. CNS Drugs 2017; 31: 135-47
Lamotrigine in women Concentrations fall with OC by as much as 50% Concentrations fall during pregnancy by 50% or more Gaffield ME et al. Contraception 2011; 83: 16-28 Pennell P et al. Neurology 2008; 70: 2130-6
LAMOTRIGINE SUBSTITUTION STUDY Carbamazepine n = 129 Phenytoin n = 92 Sodium valproate n = 117 To assess the use of lamotrigine as alternative monotherapy in patients not fully controlled on one established antiepileptic drug Brodie MJ et al. Epilepsy Research 1997; 26: 423-32
LAMOTRIGINE SUBSTITUTION STUDY Monthly seizures (Median) 10 8 6 n=92 n=129 n=68 Phenytoin Carbamazepine Sodium Valproate n=115 n=96 n=20 4 n=25 2 n=33 n=13 n=81 n=22 n=39 0 Baseline Add-on Withdrawal Monotherapy Brodie MJ et al. Epilepsy Research 1997; 26: 423-32
LAMOTRIGINE SUBSTITUTION STUDY Percentage 70 60 50 40 30 20 10 0 64% Responder rates * p < 0.001 VPA vs CBZ and PHT 41% * 38% * LTG+VPA LTG+CBZ LTG+PHT (n = 115) (n = 129) (n = 92) Brodie MJ et al. Epilepsy Research 1997; 26: 423-32
Seizure freedom on duotherapy Valproate/lamotrigine 96 Carbamazepine/valproate 26 Phenobarbital/phenytoin 24 Carbamazepine/levetiracetam 23 Carbamazepine/topiramate 20 Lamotrigine/levetiracetam 19 Valproate/levetiracetam 16 Lamotrigine/topiramate 14 Phenobarbital/carbamazepine 13 Carbamazepine/gabapentin 12 + 54 OTHER COMBINATIONS! Stephen LJ et al. Epilepsy Research 2012; 98: 194-8
Oxcarbazepine O H 3 C O O N N N O NH 2 Carbamazepine (CBZ) O NH 2 Oxcarbazepine (OXC) O NH 2 Eslicarbazepine acetate CBZ 10,11-epoxide R-licarbazepine : S-licarbazepine 1 : 4 (OXC) R-licarbazepine : S-licarbazepine 1 : 20 More predictable dose-response relationship than carbamazepine No autoinduction of metabolism Brodie MJ. CNS Drugs 2017; 31: 135-47
Oxcarbazepine Idiosyncratic reactions Hyponatraemia Teratogenesis Enzyme induction PROBLEMS ASSOCIATED WITH ITS USE Brodie MJ. CNS Drugs 2017; 31: 135-47
Rufinamide Adjunctive treatment of Lennox-Gastaut syndrome
ADJUVANT PLACEBO-CONTROLLED RUFINAMIDE STUDY Double-blind, placebo-controlled, randomized, parallel group multicentre trial of rufinamide 1600mg twice daily with an 8 week baseline and a 13 week double blind phase in adults and adolescents with refractory partial seizures Brodie MJ et al. Epilepsia 2009; 50: 1899-1909
ADJUNCTIVE PLACEBO-CONTROLLED RUFINAMIDE STUDY Median percent change in seizure frequency from baseline -25-20 -15-10 -5 0 5 * Rufinamide (n=156) *P = 0.0158 vs. placebo Placebo (n=156) Brodie MJ et al. Epilepsia 2009; 50: 1899-1909
ADJUNCTIVE PLACEBO-CONTROLLED RUFINAMIDE STUDY Median percent change in seizure frequency from baseline -35-30 -25-20 -15-10 -5 0 5 P = 0.05 P = 0.12 n = 96 n = 91 n = 60 n = 65 Rufinamide Placebo With CBZ Without CBZ Brodie MJ et al. Epilepsia 2009; 50: 1899-1909
ADJUNCTIVE PLACEBO-CONTROLLED RUFINAMIDE STUDY Median % change in seizure frequency from baseline With/without lamotrigine +6.4/-23.6 (p=0.05) With/without valproate 37.6/-13.2 (p<0.02) Brodie MJ et al. Epilepsia 2009; 50: 1899-1909 Brodie MJ et al. Presented at AAN in April 2009
Lacosamide O N H R O N Enhancement of sodium channel slow inactivation Selectively affects slow (but not fast) inactivation of the sodium channel Errington AC et al. Molecular Pharmacology 2008; 73; 157-169
Levetiracetam Lacosamide Carbamazepine Complete synergism Complete synergism Shandra P et al. Epilepsia 2013; 54: 1167-75
LACOSAMIDE RANDOMISED TRIALS Saké JK et al. CNS Drugs 2010; 24: 1055-68
LACOSAMIDE RANDOMISED TRIALS Discontinuations for common adverse events by type of comedication Discontinuation rate (%) 40 30 20 10 0 Patients comedicated with Na channel blockers 1 (n=1077) 27.6% 3.6% 5.9% 13.2% Patients comedicated with other AEDs (n=231) 2.9% 7.8% 7.2% PBO 200 400 600 PBO 200 400 600 mg/day Saké JK et al. CNS Drugs 2010;24:1055-68 6.2%
Lacosamide Allergic skin rashes Cardiac arrhythmias PROBLEMS ASSOCIATED WITH ITS USE Brodie MJ. CNS Drugs 2017; 31: 135-47
Eslicarbazepine acetate O H 3 C O O N N N O NH 2 Carbamazepine (CBZ) O NH 2 Oxcarbazepine (OXC) O NH 2 Eslicarbazepine acetate CBZ 10,11-epoxide R-licarbazepine : S-licarbazepine 1 : 4 (OXC) R-licarbazepine : S-licarbazepine 1 : 20 Modifies slow inactivated state of Na+ channel Once daily dosing CNS Drugs 2015; 29: 893-904
ESLICARBAZEPINE ACETATE Proportion of responders ( > 50% seizure reduction) 100 Proportion of responders (%) 90 ns 80 70 60 50 40 30 20 10 22.9% 36.3% P<0.0001 43.5% P<0.0001 21.5% 0 ESL 400 mg/day (n=192) ESL 800 mg/day (n=262) ESL 1,200 mg/day (n=253) Placebo (n=279) Gil-Nagel A et al. Epilepsia 2013; 54: 98-107
ESLICARBAZEPINE ACETATE Concomitant use with carbamazepine Certain adverse events eg dizziness, diplopia, abnormal co-ordination, nausea and vomiting appeared more common in eslicarbazepine acetate recipients receiving concomitant carbamazepine compared with those not taking carbamazepine Somnolence and tremor appeared less frequently with eslicarbazepine acetate 1200 mg/day in patients established on carbamazepine than those taking other antiepileptic drugs Benbadis S et al. Presented at AAN Meeting, Philadelphia 26 April 3 May, 2014
Eslicarbazepine acetate Allergic skin rashes Hyponatraemia Enzyme induction PROBLEMS ASSOCIATED WITH ITS USE Brodie MJ. CNS Drugs 2015; 11: 893-903
Conclusions There are no important differences in efficacy among the commonly used sodium channel blockers for focal and generalized tonic-clonic seizures Lamotrigine, lacosamide and possibly eslicarbazepine acetate may be better tolerated at higher doses than phenytoin, carbamazepine and oxcarbazepine and have fewer longterm problems There is a move away from prescribing enzyme inducing antiepileptic drugs in favour of noninducers SODIUM CHANNEL BLOCKERS HAVE AN ENDURING PLACE IN THE TREATMENT OF EPILEPSY INTO THE 21 ST CENTURY