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Seizure 1996; 5: 199-203

Topiramate: a new antiepileptic drug for refractory

M.C. WALKER & J.W.A.S. SANDER

Epilepsy Research Group, institute of Neurology, London & National Society for Epilepsy, Buckinghamshire, U.K.

Correspondence to: MC. Walker, Epilepsy Research Group, Institute of Neurology, Queen Square, London WClN 3BG, U.K.

Topiramate is a recently licensed and marketed antiepileptic drug in the UK for use as add-on therapy for refractory partial epilepsy. It has multiple modesof action involving voltage-dependentsodium channels,GABA receptors and glutamate receptors. Topiramate has very favourable pharmacokineticsas it is primarily excreted unchanged. Its metabolism is, however, increased by enzyme inducers, and it can inhibit the metabolism of in somepatients. Its efficacy as adjunctive treatment in refractory partial epilepsy in adults appearsgood, over 40% of patients have a 50% or greater reduction in seizure frequency when topiramate is added to their regime with up to 7% becoming seizure free. The main adverse events are , impaired concentration, confusion, dizziness,fatigue, parasthesia,somnolence and ‘thinking abnormal’. Most of theseoccurred during rapid titration. During long-term treatment, weight lossalso occurred and nephrolithiasisoccurred in 1.5% of patients receiving topiramate. Topiramate is a useful and well-tolerated addition to our treatment of refractory epilepsy,but it shouldbe titrated slowly in order to avoid adverseevents.

Key worh: refractory epilepsy; new antiepileptic drug; topiramate.

INTRODUCTION unfortunately much of the information on the drug has been gleaned from personal knowledge, abstracts and product monographs. There are two main reasons for new antiepileptic drug (AED) development: (1) to develop AEDs for use in patients with epilepsy resistant to available AEDs and (2) to develop AEDs with MECHANISM OF ACTION better side-effect and pharmacokinetic profiles than currently available AEDs. Approximately Topiramate (2,3;4,5-bis-O-(l-methylidene)-beta- 20% of patients with epilepsy are resistant to D-fractopyranose sulphamate) is a sulphamate- therapy with first line AED treatment and only substituted monosaccharide which exhibits some the minority of these patients are amenable to inhibition of carbonic anhydrase, but whose epilepsy surgery’. The effect of new AEDs on the action is likely to be independent of this effect. prognosis of this population group has been Acetazolamide-tolerant mice are not tolerant to disappointing, and new, more effective AEDs are topiramate, implying that these AEDs act by still required2. Topiramate is a recently licensed different mechanisms3. It is effective against and marketed (October 1995) AED in the UK for maximal electroshock, but not chemically- use as add-on therapy for partial seizures with or induced seizures in rats, and thus in animal without secondarily generalized seizures in pati- models has a similar spectrum of activity to ents inadequately controlled on conventional first phenytoin3. Topiramate appears to have multiple line antiepileptic treatment. Despite its recent modes of action. It acts at voltage-dependent marketing, there is still a dearth of information on sodium channels blocking the spread of seizures4, topiramate in peer-reviewed journals and thus it enhances GABAA evoked chloride currents at

1059-1311/96/030199+05 $12.00/O 0 1996 British Epilepsy Association M.C. Walker & J.W.A.S. Sander a non- receptor site’ and it an- EFFICACY IN HUMANS tagonises AMPA subtype glutamate receptors6. The role of this latter mechanism is still unclear. Preliminary results from trials suggest that topiramate is useful in partial seizures and in patients with Lennox-Gastaut syndrome’8-22. In these trials doses of up to 1800 mg/day were well tolerated, and in the USA trials are underway In healthy volunteers, topiramate is well ab- with doses as high as 48OOmgldap. Five sorbed following oral ingestion with a time to double-blind, placebo-controlled, randomized maximum concentration of 2-4 hours’. The rate trials of topiramate (200-1000 mg) as add-on in of absorption may be slowed by food, but the refractory partial epilepsy (total of 534 patients) extent of absorption remains unchanged’. It has have been carried out in the US and Europe24. minimal binding to plasma proteins (15%). It has Topiramate produced a significant reduction in linear and predictable pharmacokinetics, and it is secondarily generalized, complex partial and predominantly excreted unchanged in the urine simple partial seizure rates. Significantly more with an elimination half-life of 19-23 hours’. patients (19%) on topiramate than placebo had a Topiramate does however undergo some meta- 75% reduction in seizures, and significantly more bolism and the plasma concentrations and half- became seizure free (4%)*“. This last figure life of topiramate are reduced by phenytoin, and compares well with a meta-analysis of other new ”‘. Topiramate should thus be drugs in which less than 2% of patients became taken at least twice daily. seizure free*. Responder rates (patients with a Topiramate has no effect on the plasma 50% or greater reduction in seizures) in the concentrations of carbarnazepine’O. There is some European double blind studies were 35% for evidence that the area under the concentration vs. 400 mg/day, 47% for 600 mg/daJ6 and 43% for time curve for phenytoin is greater with co- 800 mg/daf’. In this last trial 7% became seizure administration of topiramate in a few patients”. free*‘. In a novel trial design, topiramate low dose This interaction is possibly due to topiramate (100 mg/day) was compared with topiramate high inhibiting the uncommon CYP2C19 isoform of dose (1000 mg/day) in a double-blind fashion in cytochrome P45013. This isoform has other patients with refractory epilepsy who had had substrates such as and omeprazole, and their concomitant AEDs withdrawn=. This trial thus topiramate could inhibit the metabolism of lasted 112 days, but patients were withdrawn these”. However, topiramate does not inhibit any from the trial if they met any of a set of criteria other CYP450 isoforms and thus would be that were used to determine if seizure control had expected to have very few inhibition based drug deteriorated from baseline. Overall, time to interactionsX3. In patients with epilepsy, there withdrawal was longer for those taking appears to be no clinically significant interaction 1000 mg/day topiramate and significantly more of between valproic acid and topiramate14. How- this group completed the trialz. ever, topiramate does induce a significant change in the metabolic profile, a fall in glucuronide conjugates was accompanied by a TOLERABILITY AND SAFETY small increase in oxidative metabolites of valproate15. The significance of this is unknown. There has been over 2000-person years of There is an interaction with the contraceptive pill; experience with topiramate and it appears to be contraceptive pills containing at least 50 pg of well tolerated6. Overall in the double blind oestrogen should be used6. There is no correla- studies ataxia, impaired concentration, confusion, tion between plasma concentrations and either dizziness, fatigue, parasthesia, somnolence and median percent reduction in seizure rates or ‘thinking abnormal’ occurred in 5% or more percentage responders16. Statistically significant patients6. Over 80% of patients who experienced increases in mean plasma concentrations oc- adverse events during titration did not continue curred in patients experiencing weight loss and to report these events by the fourth month6. Thus anorexia, and there was a trend towards higher many of these adverse events may have been due plasma concentrations for those experiencing to the rapid (3-6 week) titration that occurred adverse events16. Thus overall topiramate has during these trials. During long-term treatment favourable pharmacokinetics, which compare weight loss also occurred, this happened in the well with recently licensed AEDs, and AEDs first three months of treatment and peaked by presently still under development”. 12-15 months of treatment6. Topiramate: a new AED for refractory epilepsy 201

Nephrolithiasis occurred in 1.5% of patients a maximum dose of 8OOmg/day. Some patients treated with topiramate; the annual incidence is require an even slower titration, and certainly similar to that of nephrolithiasis caused by those patients who are not taking an enzyme acetazolamide*‘. In cases where analysis was inducer could benefit from an initial starting dose performed the stones were primarily calcium of 25-50 mg/day increasing by 25-50 mg/day phosphate stones. The mechanism of action of increments weekly up to 200 mg/day in divided nephrolithiasis caused by topiramate is likely to doses. Thereafter increments of 100 mg/day be related to decreased citrate excretion3’. So far weekly should be used up to a maximum dose of no other serious idiosyncratic reactions to topira- 8OOmg/day. Patients with renal impairment mate have been identified. require a slower titration (2 weekly increments) Teratogenic effects of topiramate have been and will generally require lower doses”. Hepatic noted in animal models and are similar to those impairment has only a minimal effect on topiram- observed with acetazolamide. They mainly con- ate kinetics, as does age6. Patients on phenytoin sist of skeletal malformations including: right- should have their phenytoin plasma concentra- sided ectrodactyl and rib and vertebral malfor- tions monitored. Withdrawal of topiramate mations in rabbit@. should occur by lOOmg/day weekly, although The total withdrawal rate due to adverse events faster withdrawal rates have been tolerated. in the double-blind studies was approximately 14% with the majority of these withdrawals occurring during the titration phase”. This figure CONCLUSION is higher than that seen in the double-blind trials of , and lamotrigine31, and it may be related to the titration rate of topiramate Topiramate is a new AED with a novel mechan- being too rapid, although this requires further ism of action and favourable pharmacokinetics. investigation. Its tested efficacy as adjunctive treatment in Carbonic anhydrase inhibitors can produce refractory partial epilepsy in clinical trials com- gastric hyperplasia, by decreasing gastric acid pares with other new AEDs. There have also secretion and consequently causing increased been reports of its effectiveness in Lennox- gastrin levels. Topiramate, however, did not have Gastaut and other epilepsy syndromes, although significant gastrointestinal adverse events6 and the results of trials in these patient groups are furthermore an endoscopic study in eight patients awaited. Topiramate predominantly has CNS on long-term topiramate treatment (3 years) side-effects that are common to most AEDs, and demonstrated no effect of topiramate on gastric these adverse events usually occurred during levels or gastric mucosal histology*. rapid titration. During double-blind trial, with- Topiramate has also been used in children and drawal rates due to adverse events appeared to be has been found to be safe, well-tolerated and easy slightly greater than that seen with other new to titrate33. In one paediatric trial, topiramate was AEDs, but again this may be related to rapid introduced at a dose of 1 mg/kg/day for the first titration. Renal stones occurred in approximately week increasing to 3mg/kg/day for the second 1.5% of patients (i.e. with a similar frequency in week, 6 mg/kg/day for the third week and then acetazolamide). finally 9 mg/kg/day for the fourth week33. Topiramate appears to be an effective and well-tolerated addition to our range of AEDs. However, as with all new AEDs, a number of CLINICAL USE caveats need to be made. The first is that the development of tolerance and some long-term Topiramate is available in 25 mg, 50 mg, 100 mg side-effects may not be evident because of the and 200 mg tablets. The minimal effective dose time limit imposed on AED trials. The second is appears to be 200 mg and most patients will need that the total number of patients included in 200-6OOmg/day in divided doses. During the AED trials is relatively small, and thus rare but trials, withdrawals and adverse events may have clinically important side-effects like, for example, been due to rapid titration of topiramate, and it aplastic anaemia may be missed (as occurred with should thus be titrated slowly. The recommended the new AED ). Thirdly, new AED starting dose is lOOmg/day in divided doses trials exclude pregnant patients or those on increasing after one week to 2OOmg/day in inadequate contraception, and thus there are divided doses. Thereafter the dose can be scarce data on the safety of new AEDs during increased by 200 mg/day increments weekly up to pregnancy and on the developing foetus. Lastly, 202 MC. Walker & J.W.A.S. Sander drug trials are performed in selected population epileptic patients receiving carbamazepine. Epilepsia and the drug could have a different side-effect and 1989; 30: 645. tolerability profile in different population groups. 12. Gisclon, L.G., Curtin, C.R. and Kramer, L.D. The steady-state phannacokinetics of phenytoin (dilantin) and These problems emphasise the importance of topiramate (topamax) in epileptic patients on monothe- case reporting and notification in early and even rapy and during combination therapy. Epilepsia 1994; 35 late post-marketing phases. The eventual role of (Suppl. 8): 554. topiramate (as, indeed, most new AEDs) in the 13. Levy, R.H., Bishop, F., Streeter, A.J. et al. Explanation treatment of epilepsy remains to be determined, and prediction of drug interactions with topiramate using a CYP450 inhibition spectrum. Epilepsia 1995; 36 (Suppl. and only clinical experience over many years will 4): 547. answer this question. Topiramate does, however, 14. Liao, S., Rosenfeld, W.E., Palmer, M. et al. Steady-state appear to be a useful addition to the treatment of pharmacokinetics of topiramate and valproic acid in refractory epilepsy. patients with epilepsy on monotherapy and during combination therapy. Epilepsia 1994; 35 (Suppl. 8): 5117. 15. Bourgeois, B.F. profile of topiramate. ACKNOWLEDGEMENT Clinical courier 1995; 13: 4-5. 16. Reife, R.A., Pledger, G., Doose, D., Lim, P. and Ward, C. Topiramate PK/PD analyses. Epilepsia 195; 36 (Suppl. 3): We would like to thank the Wellcome Trust for S152. supporting the work of Dr Walker. 17. Walker, M.C. and Patsalos, P.N. Clinical phar- macokinetics of new antiepileptic drugs. Pharmacology and Therapeutics 1995; 67: 351-384. 18. Sharief, M.W., Sander, J.W.A.S., Patsalos, P.N. and REFERENCES Shorvon, S.D. Double blind parallel comparison of topiramate with placebo in patients with refractory partial epilepsy. Seizure 1992; 1 (Suppl. A): F’7/45. 1. Walker, M.C. and Sander, J.W.A.S. Overtreatment with 19. Sharief, M.W., Sander, J.W.A.S. and Shorvon, S.D. antiepileptic drugs: how extensive is the problem? CNS Long-term treatment with topiramate in refractory partial Drugs 1994; 2: 335-340. epilepsy: two-year follow-up study. Seizure 1992; 1 (Suppl. 2. Walker, M.C. and Sander, J.W.A.S. The impact of new A): F’7/47. antiepileptic drugs on the prognosis of epilepsy: seizure 20. Mikkelsen, M., Dam, M. and Ostergaard, L. Topiramate freedom should be the ultimate goal. Neurology 1996; 46: as add-on therapy in refractory partial seizures. Seizure 912-914. 1992; 1 (Suppl. A): W/31. 3. Shank, R.P., Gardocki, J.F., Vaught, J.L. et al. 21. Engelskjon, T., Johannessen, S.I., Kloster, R. et al. Topiramate: preclinical evaluation of a structurally novel Topiramate in the treatment of refractory partial . Epilepsia 1994; 35: 450-460. epilepsy-an efficacy and tolerance study. Seizure 1992; 1 4. Coulter, D.A., Sombati, S. and DeLorenzo, R.J. Selective (Suppl. A): p7/K. effects of topiramate on sustained repetitive firing and 22. Espe-Lillo, J., Ritter, F.J., Frost, M.D., Spiegel, R.H. and spontaneous bursting in cultured hippocampal neurons. Reife, R. Safety and efficacy of topiramate in pediatric Epilepsia 1993; 34 (Suppl 2): S123. subjects. Epilepsia 1994; 35 (Suppl. 8): S162. 5. Brown, S.D., Wolf, H.H., Swinyard, E.A., Twyman, R.E. 23. French, J. New AED options: clinical efficacy-the US and White, H.S. The novel anticonvulsant topiramate experience. Clinical courier 1995; 13: 7-8. enhances GABA-mediated chloride flux. Epilepsia 1993; 24. Pledger, G., Reife, R.A., Lim, P. and Karim, R. Overview 34 (Suppl. 2): 5122-5123. of topiramate efficacy from adjunctive therapy trials. 6. Topamar product monograph. Cheshire, Gardiner- Epilepsia 1995; 36 (Suppl. 3): S150. Caldweh Communications Ltd, 1995. 25. Martinez-Lage, J., Ben-Menachem, E., Shorvon, S.D. and 7. Easterhng, D.E., Zakszewski, T., Moyer, M.D., Margul, Weber, M. Double-blind, placebo-controlled trial of B.L., Marriott, T.B. and Nayak, R.K. Multiple dose 400 mg/day topiramate as add-on therapy in patients with pharmacokinetics of topiramate in healthy male subjects. refractory partial epilepsy. Epilepsia 1995; 36 (Suppl. 3): Epilepsia 1988; 29: 662. s149. 8. Doose, D.R., Gisclon, L.G., Stellar, S.M., Riftits, J.M. 26. Tassinari, C., Chauvel, P., Chodkiewicz, J. et al. and Hills, J.F. The effect of food on the bioavailability of Double-blind, placebo-controlled trial of 600 mg/day topiramate from 1CtO-4CKlmg tablets in healthy male topiramate as add-on therapy in patients with refractory subjects. Epilepsia 1992; 33 (Suppl. 3): S105. partial epilepsy. Epilepsia 1995; 35 (Suppl. 3): S150. 9. Floren, K.L., Graves, N.M., Leppik, I.E., Remmel, R.P., 27. Ben-Menachem, E., Dam, M., Henrikson, 0. and Margul, B. and Doose, D.R. Pharmacokinetics of Schmidt, D. Double-blind, placebo-controlled trial of topiramate in patients with partial epilepsy receiving 800 mg/day topiramate as add-on therapy in patients with phenytoin or valproic acid. Epilepsia 1989; 30: 646. refractory partial epilepsy. Epilepsia 1995; 36 (Suppl. 3): 10. Doose, D., Walker, S.A., Sachdeo, R., Kramer, L.D. and s150. Nayak, R.K. Steady-state pharmacokinetics of tegretol 28. Sachdeo, S.K., Sachdeo, R.C., Reife, R.A., Lim, P. and (carbamazepine) and topamax (topiramate) in patients Pledger, G. Topiramate; double-blind trial as monothe- with epilepsy on monotherapy, and during combination rapy. Epilepsia 1995; 36 (Suppl. 4): S33. therapy. Epilepsia 1994; 35 (Suppl. 8): 554. 29. Wasserstein, A.G., Rak, I. and Reife, R.A. Nephrolithi- 11. Wilensky, A.J., Ojermann, L.M., Chmelir, T., Ma@, asis during treatment with topiramate. Epilepsia 1995; 36 B.L. and Doose, D.R. Topiramate pharmacokinetics in (Suppl. 3): s153. Topiramate: a new AED for refractory epilepsy 203

30. Wasserstein, A.G., Rak, I. and Reife, R.A. Investigation 32. Ben-Menachem, E. and Abrahamsson, H. Gastroscopic of the mechanistic basis for topiramate-associated neph- evaluation of patients with complex partial seizures rolithiasis: examination of urinary and serum constituents. treated with topiramate. Epilepsia 1994; 35 (Suppl. 8): Epiiepsia 1995; 36 (Suppl. 3): S153. S116. 31. Walker, M.C. and Patsalos, P.N. The safety and 33. Thanedar, S., Rosenfeld, W.E. and Doose, D. Topiramate tolerability of gabapentin. Reviews of Contemporary well tolerated by pediatric patients. Epilepsia 1995; 36 Pharmacotherapy 1996; (in press). (Suppl. 4): s34.