Summary
Therapy with traditional antiepileptic drugs is associated with a wide range of pharmacokinetic drug-drug interactions. In particular, enzyme induction, enzyme inhibition and displacement from protein binding may result in important changes in serum concentrations of antiepileptics. Relevant interactions have also been described for some new antiepileptics.
Felbamate increases serum concentrations of phenytoin, phenobarbital and valproic acid (sodium valproate). On the other hand, it reduces concentrations of carbamazepine and increases concentrations of its metabolite carbamazepine-10,11-epoxide. Concentrations of felbamate itself are reduced by phenytoin and carbamazepine. Concentrations of lamotrigine are considerably increased by valproic acid and decreased by phenytoin, carbamazepine and phenobarbital (phenobarbitone). Vigabatrin reduces serum concentrations of phenytoin by approximately 20%.
On the other hand, some new antiepileptics have the important advantage of not interfering with the metabolism of other antiepileptics; this is the case for gabapentin, lamotrigine and oxcarbazepine. Furthermore, the pharmacokinetics of gabapentin, oxcarbazepine and vigabatrin are independent of concomitant drugs. These aspects are especially important as, until now, new antiepileptics have been most often utilised as add-on therapy.
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References
Patsalos PN, Duncan JS. Antiepileptic drugs: a review of clinically significant drug interactions. Drug Saf 1993; 9: 156–84
Theodore WH, Jensen PK, Kwan RMR. Felbamate: clinical use. In: Levy RH, Mattson RH, Meldrum BS, editors. Antiepileptic drugs. New York: Raven Press, 1995: 817–22
Leppik IE. Felbamate. Epilepsia 1995; 36 Suppl. 2: 66–72
Perucca E. The clinical pharmacology of the new antiepileptic drugs. Pharmacol Res 1993; 28: 89–106
Wilensky AJ, Friel PN, Ojemann LM, et al. Pharmacokinetics of W-554 (ADD 03055) in epileptic patients. Epilepsia 1985; 26: 602–6
Fuerst RH, Graves NM, Leppik IE, et al. Felbamate increases phenytoin but decreases carbamazepine concentrations. Epilepsia 1988; 29: 488–91
Graves NM, Holmes GB, Fuerst RH, et al. Effect of felbamate on phenytoin and carbamazepine serum concentrations. Epilepsia 1989; 30: 225–9
Theodore WH, Raubertas RF, Porter RJ, et al. Felbamate: a clinical trial for complex partial seizures. Epilepsia 1991; 32: 392–7
Albani F, Theodore WH, Washington P, et al. Effect of felbamate on plasma levels of carbamazepine and its metabolites. Epilepsia 1991; 32: 130–2
Wagner ML, Remmel RP, Graves NM, et al. Effect of felbamate on carbamazepine and its major metabolites. Clin Pharmacol Ther 1993; 53: 536–43
Reidenberg P, Glue P, Banfield CR, et al. Effects of felbamate on the pharmacokinetics of phenobarbital. Clin Pharmacol Ther 1995; 58: 279–87
Wagner ML, Graves NM, Leppik IE, et al. The effect of felbamate on valproic acid disposition. Clin Pharmacol Ther 1994; 56: 494–502
Hooper WD, Franklin ME, Glue P, et al. Effect of felbamate on valproic acid disposition in healthy volunteers: inhibition of β-oxidation. Epilepsia 1996; 37: 91–7
Bernus I, Dickinson RG, Hooper WD, et al. Effect of felbamate on the plasma protein binding of valproate. Clin Drug Invest 1995; 10: 288–95
Reidenberg P, Glue P, Banfield C, et al. Pharmacokinetic interaction studies between felbamate and vigabatrin. Br J Clin Pharmacol 1995; 40: 157–60
Hulsman JARJ, Rentmeester TW, Banfield CR, et al. Effects of felbamate on the pharmacokinetics of the monohydroxy and dihydroxy metabolites of oxcarbazepine. Clin Pharmacol Ther 1995; 58: 383–9
Saano V, Glue P, Banfield CR, et al. Effects of felbamate on the pharmacokinetics of low-dose combination oral contraceptive. Clin Pharmacol Ther 1995; 58: 523–31
Wagner ML, Graves NM, Marienau K, et al. Discontinuation of phenytoin and carbamazepine in patients receiving felbamate. Epilepsia 1991; 32: 398–406
Wagner ML, Leppik IE, Graves NM, et al. Felbamate serum concentrations: effect of valproate, carbamazepine, phenytoin and phenobarbital [abstract]. Epilepsia 1990; 31: 642
Brodie MJ. Felbamate: a new antiepileptic drug. Lancet 1993; 341: 1445–6
Burdette DE, Sackellares JC. Felbamate pharmacology and use in epilepsy. Clin Neuropharmacol 1994; 17: 389–402
Graves NM. Felbamate. Ann Pharmacother 1993; 27: 1073–81
Palmer KJ, McTavish D. Felbamate: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in epilepsy. Drugs 1993; 45: 1041–65
Goa KL, Sorkin EM. Gabapentin: a review of its pharmacological properties and clinical potential in epilepsy. Drugs 1993; 46: 409–27
Hooper WD, Kavanagh MC, Herkes GK, et al. Lack of a pharmacokinetic interaction between phenobarbitone and gabapentin. Br J Clin Pharmacol 1991; 31: 171–4
Crawford P, Ghadiali E, Lane R, et al. Gabapentin as an antiepileptic drug in man. J Neurol Neurosurg Psychiatry 1987; 50: 682–6
Radulovic LL, Wilder BJ, Leppik IE, et al. Lack of interaction of gabapentin with carbamazepine or valproate. Epilepsia 1994; 35: 155–61
US Gabapentin Study Group. The long-term safety and efficacy of gabapentin (Neurontin®) as add-on therapy in drug-resistant partial epilepsy. Epilepsy Res 1994; 18: 67–73
Tyndel F. Interaction of gabapentin with other antiepileptics. Lancet 1994; 343: 1363–4
Eldon MA, Underwood BA, Randinitis EJ, et al. Lack of effect of gabapentin on the pharmacokinetics of a norethindrone acetate/ethinyl estradiol-containing oral contraceptive [abstract]. Neurology 1993; 43: A307–A8
McLean MJ. Clinical pharmacokinetics of gabapentin. Neurology 1994; 44 Suppl. 5: 17–22
Ramsay RE. Clinical efficacy and safety of gabapentin. Neurology 1994; 44 Suppl. 5: 23–30
Busch JA, Radulovic LL, Bockbrader HN, et al. Effect of maalox TC on single-dose pharmacokinetics of gabapentin capsules in healthy subjects [abstract]. Pharm Res 1992; 9 Suppl. 2: S315
Goa KL, Ross SR, Chrisp P. Lamotrigine: a review of its pharmacological properties and clinical efficacy in epilepsy. Drugs 1993; 46: 152–76
Timmings PL, Richens A. Lamotrigine in primary generalised epilepsy. Lancet 1992; 339: 1300–1
Ferrie CD, Robinson RO, Knott C, et al. Lamotrigine as an add-on drug in typical absence seizures. Acta Neurol Scand 1995; 91: 200–2
Jawad S, Yuen WC, Peck AW, et al. Lamotrigine: single-dose pharmacokinetics and initial 1 week experience in refractory epilepsy. Epilepsy Res 1987; 1: 194–201
Loiseau P, Yuen AWC, Duche B, et al. A randomised double-blind placebo-controlled crossover add-on trial of lamotrigine in patients with treatment-resistant partial seizures. Epilepsy Res 1990; 7: 136–45
Sander JWAS, Patsalos PN, Oxley JR, et al. A randomized double-blind placebo-controlled add-on trial of lamotrigine in patients with severe epilepsy. Epilepsy Res 1990; 6: 221–6
Jawad S, Richens A, Goodwin G, et al. Controlled trial of lamotrigine (Lamictal®) for refractory partial seizures. Epilepsia 1989; 30: 356–63
Schapel GJ, Beran RG, Vajda FJE, et al. Double-blind, placebo controlled, crossover study of lamotrigine in treatment resistant partial seizures. J Neurol Neurosurg Psychiatry 1993; 56: 448–53
Posner J, Webster H, Yuen WC. Investigation on the ability of lamotrigine, a novel antiepileptic drug, to induce mixed function oxygenase enzymes. Br J Clin Pharmacol 1991; 32: 658
Warner T, Patsalos PN, Prevett M, et al. Lamotrigine-induced carbamazepine toxicity: an interaction with carbamazepine-10,11-epoxide. Epilepsy Res 1992; 11: 147–50
Wolf P. Lamotrigine: preliminary clinical observations on pharmacokinetics and interactions with traditional antiepileptic drugs. J Epilepsy 1992; 5: 73–9
Pisani F, Xiao B, Fazio A, et al. Single dose pharmacokinetics of carbamazepine-10,11-epoxide in patients on lamotrigine monotherapy. Epilepsy Res 1994; 19: 245–8
Buchanan N. Lamotrigine: clinical experience in 93 patients with epilepsy. Acta Neurol Scand 1995; 92: 28–32
Holdich T, Whiteman P, Orme M, et al. Effect of lamotrigine on the pharmacology of the combined oral contraceptive pill [abstract]. Epilepsia 1991; 32 Suppl. 1: 96
Binnie CD, van Emde Boas W, Kasteleijn-Nolste-Trenite DGA, et al. Acute effects of lamotrigine (BW430C) in persons with epilepsy. Epilepsia 1986; 27: 248–54
Yuen AWC, Land G, Weatherley BC, et al. Sodium valproate acutely inhibits lamotrigine metabolism. Br J Clin Pharmacol 1992; 33: 511–3
May TW, Rambeck B, Jürgens U. Serum concentrations of lamotrigine in epileptic patients: the influence of dose and comedication. Ther Drug Monit 1996 Autumn; 18. In press
Depot M, Powell JR, Messenheimer JA, et al. Kinetic effects of multiple oral doses of acetaminophen on a single oral dose of lamotrigine. Clin Pharmacol Ther 1990; 48: 346–55
Panayiotopoulos CP, Ferrie CD, Knott C, et al. Interaction of lamotrigine with sodium valproate. Lancet 1993; 341: 445
Ferrie CD, Panayiotopoulos CP. Therapeutic interaction of lamotrigine and sodium valproate in intractable myoclonic epilepsy. Seizure 1994; 3: 157–9
Pisani F, Di Perri R, Perucca E, et al. Interaction of lamotrigine with sodium valproate. Lancet 1993; 341: 1224
Pisani F, Oteri G, Russo M, et al. Effects of lamotrigine-valproate comedication on seizure frequency and upper limb tremor: a pharmacodynamic interaction? [abstract]. Epilepsia 1995; 36 Suppl. 3: S264
Reutens DC, Duncan JS, Patsalos PN. Disabling tremor after lamotrigine with sodium valproate. Lancet 1993; 342: 185–6
Brodie MJ. Lamotrigine. Lancet 1992; 339: 1397–400
Rambeck B, Wolf P. Lamotrigine clinical pharmacokinetics. Clin Pharmacokinet 1993; 25: 433–43
Messenheimer JA. Lamotrigine. Clin Neuropharmacol 1994; 17: 548–59
Messenheimer JA. Lamotrigine. Epilepsia 1995; 36 Suppl. 2: 87–94
Burstein AH. Lamotrigine. Pharmacotherapy 1995; 15: 129–43
Grant SM, Faulds D. Oxcarbazepine: a review of its pharmacology and therapeutic potential in epilepsy, trigeminal neuralgia and affective disorders. Drugs 1992; 43: 873–88
McKee PJW, Blacklaw J, Forrest G, et al. A double-blind, placebo-controlled interaction study between oxcarbazepine and carbamazepine, sodium valproate and phenytoin in epileptic patients. Br J Clin Pharmacol 1994; 37: 27–32
Battino D, Croci D, Granata T, et al. Changes in unbound and total valproic acid concentrations after replacement of carbamazepine with oxcarbazepine. Ther Drug Monit 1992; 14: 376–9
Houtkooper MA, Lammertsma A, Meyer JWA, et al. Oxcarbazepine (GP 47.680): a possible alternative to carbamazepine? Epilepsia 1987; 28: 693–8
Larkin JG, McKee PJW, Forrest G, et al. Lack of enzyme induction with oxcarbazepine (600mg daily) in healthy subjects. Br J Clin Pharmacol 1991; 31: 65–71
Krämer G, Tettenborn B, Klosterskov Jensen P, et al. Oxcarbazepine does not affect the anticoagulant activity of warfarin. Epilepsia 1992; 33: 1145–8
Lloyd P, Flesch G, Dieterle W. Clinical pharmacology and pharmacokinetics of oxcarbazepine. Epilepsia 1994; 35 Suppl. 3: 10–3
Klosterskov Jensen P, Saano V, Haring P, et al. Possible interaction between oxcarbazepine and an oral contraceptive. Epilepsia 1992; 33: 1149–52
Zaccara G, Gangemi PF, Bendoni L, et al. Influence of single and repeated doses of oxcarbazepine on the pharmacokinetic profile of felodipine. Ther Drug Monit 1993; 15: 39–42
Patsalos PN, Zakrzewska JM, Elyas AA. Dose dependent enzyme induction by oxcarbazepine. Eur J Clin Pharmacol 1990; 39: 187–8
Tartara A, Galimberti CA, Manni R, et al. The pharmacokinetics of oxcarbazepine and its active metabolite 10-hydroxy-carbazepine in healthy subjects and in epileptic patients treated with phenobarbitone or valproic acid. Br J Clin Pharmacol 1993; 36; 366–8
Arnoldussen W, Hulsman J, Rentmeester T. Interaction between oxcarbazepine and phenytoin [abstract]. Epilepsia 1993; 34 Suppl. 6: 37
Kumps A, Wuth C. Oxcarbazepine disposition: preliminary observations in patients. Biopharm Drug Dispos 1990; 11: 365–70
Keränen T, Jolkkonen J, Jensen PK, et al. Absence of interaction between oxcarbazepine and erythromycin. Acta Neurol Scand 1992; 86: 120–3
Keränen T, Jolkkonen J, Klosterskov-Jensen P, et al. Oxcarbazepine does not interact with cimetidine in healthy volunteers. Acta Neurol Scand 1992; 85: 239–42
Mogensen PH, Jorgensen L, Boas J, et al. Effects of dextropropoxyphene on the steady-state kinetics of oxcarbazepine and its metabolites. Acta Neurol Scand 1992; 85: 14–7
Pisani F, Fazio A, Oteri G, et al. Effects of the antidepressant drug viloxazine on oxcarbazepine and its hydroxylated metabolites in patients with epilepsy. Acta Neurol Scand 1994; 90: 130–2
Krämer G, Tettenborn B, Flesch G. Oxcarbazepine-verapamil drug interaction in healthy volunteers [abstract]. Epilepsia 1991; 32 Suppl. 1: 70–1
Faigle JW, Menge GP. Pharmacokinetic and metabolic features of oxcarbazepine and their clinical significance: comparison with carbamazepine. Int Clin Psychopharmacol 1990; 5: 73–82
Baruzzi A, Albani F, Riva R. Oxcarbazepine: pharmacokinetic interactions and their clinical relevance. Epilepsia 1994; 35 Suppl. 3: 14–9
Grant SM, Heel RC. Vigabatrin: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in epilepsy and disorders of motor control. Drugs 1991; 41: 889–926
Rimmer EM, Richens A. Double-blind study of γ-vinyl GABA in patients with refractory epilepsy. Lancet 1984; 1: 189–90
Browne TR, Mattson RH, Penry JK, et al. Vigabatrin for refractory complex partial seizures: multicenter single-blind study with long-term follow-up. Neurology 1987; 37: 184–9
Browne TR, Mattson RH, Penry JK, et al. A multicentre study of vigabatrin for drug-resistant epilepsy. Br J Clin Pharmacol 1989; 27 Suppl. 1: 95–100
Dalla Bernardina B, Fontana E, Vigevano F, et al. Efficacy and tolerability of vigabatrin in children with refractory partial seizures: a single-blind dose-increasing study. Epilepsia 1995; 36: 687–91
Rimmer EM, Richens A. Interaction between vigabatrin and phenytoin. Br J Clin Pharmacol 1989; 27: S27–S33
Gatti G, Bartoli A, Marchiselli R, et al. Vigabatrin-induced decrease in serum phenytoin concentration does not involve a change in phenytoin bioavailability. Br J Clin Pharmacol 1993; 36: 603–6
Armijo JA, Arteaga R, Valdizán EM, et al. Coadministration of vigabatrin and valproate in children with refractory epilepsy. Clin Neuropharmacol 1992; 15: 459–69
Gram L, Klosterskov P, Dam M. γ-Vinyl GABA: a double-blind placebo-controlled trial in partial epilepsy. Ann Neurol 1985; 17: 262–6
Loiseau P, Hardenberg JP, Pestre M, et al. Double-blind, placebo-controlled study of vigabatrin (Gamma-Vinyl GABA) in drug-resistant epilepsy. Epilepsia 1986; 27: 115–20
Luna D, Dulac O, Pajot N, et al. Vigabatrin in the treatment of childhood epilepsies: a single-blind placebo-controlled study. Epilepsia 1989; 30: 430–7
Matilainen R, Pitkänen A, Ruutiainen T, et al. Effect of vigabatrin on epilepsy in mentally retarded patients: a 7-month follow-up study. Neurology 1988; 38: 743–7
Cocito L, Maffini M, Perfumo P, et al. Vigabatrin in complex partial seizures: a long-term study. Epilepsy Res 1989; 3: 160–6
Szylleyko OJ, Hoke JF, Eller MG, et al. A definitive study evaluating the pharmacokinetic of vigabatrin in patients with epilepsy [abstract]. Epilepsia 1993; 34 Suppl. 6: 41–2
Ben-Menachem E. Vigabatrin. Epilepsia 1995; 36 Suppl. 2: 95–104
Rey E, Pons G, Olive G. Vigabatrin: clinical pharmacokinetics. Clin Pharmacokinet 1992; 23: 267–78
Richens A. Pharmacology and clinical pharmacology of vigabatrin. J Child Neurol 1991; 6 Suppl. 2: S7–S10
Richens A. Pharmacokinetic and pharmacodynamic drug interactions during treatment with vigabatrin. Acta Neurol Scand 1995; Suppl. 162: 43–6
Sabers A, Gram L. Pharmacology of vigabatrin. Pharmacol Toxicol 1992; 70: 237–43
Peters DH, Sorkin EM. Zonisamide: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in epilepsy. Drugs 1993; 45: 760–87
Sackellares JC, Donofrio PD, Wagner JG, et al. Pilot study of zonisamide (1,2-benzisoxazole-3-methanesulfonamide) in patients with refractory partial seizures. Epilepsia 1985; 26: 206–11
Minami T, Ieiri I, Ohtsubo K, et al. Influence of additional therapy with zonisamide (excegran) on protein binding and metabolism of carbamazepine. Epilepsia 1994; 35: 1023–5
Browne TR, Szabo GK, Kres J, et al. Drug interactions of zonisamide (DI-912) with phenytoin and carbamazepine [abstract]. J Clin Pharmacol 1986; 26: 555
Schmidt D, Jacob R, Loiseau P, et al. Zonisamide for add-on treatment of refractory partial epilepsy: a European double-blind trial. Epilepsy Res 1993; 15: 67–73
Tasaki K, Minami T, Ieiri I, et al. Drug interactions of zonisamide with phenytoin and sodium valproate: serum concentrations and protein binding. Brain Dev 1995; 17: 182–5
Ojemann LM, Shastri RA, Wilensky AJ, et al. Comparative pharmacokinetics of zonisamide (CI-912) in epileptic patients on carbamazepine or phenytoin monotherapy. Ther Drug Monit 1986; 8: 293–6
Kimura M, Tanaka N, Kimura Y, et al. Factors influencing serum concentration of zonisamide in epileptic patients. Chem Pharm Bull 1992; 40: 193–5
Stables JP, Bialer M, Johannessen SI, et al. Progress report on new antiepileptic drugs: a summary of the Second Eilat Conference. Epilepsy Res 1995; 22: 235–46
Britton JW, So EL. New antiepileptic drugs: prospects for the future. J Epilepsy 1995; 8: 267–81
Walker MC, Patsalos PN. Clinical pharmacokinetics of new antiepileptic drugs. Pharmacol Ther 1995; 67: 351–84
Gustavson LE, Mengel HB. Pharmacokinetics of tiagabine, a γ-aminobutyric acid-uptake inhibitor, in healthy subjects after single and multiple doses. Epilepsia 1995; 36: 605–11
Richens A, Chadwick DW, Duncan JS, et al. Adjunctive treatment of partial seizures with tiagabine: a placebo-controlled trial. Epilepsy Res 1995; 21: 37–42
Brodie MJ. Tiagabine pharmacology in profile. Epilepsia 1995; 36 Suppl. 6: S7–S9
So EL, Wolff D, Graves NM, et al. Pharmacokinetics of tiagabine as add-on therapy in patients taking enzyme-inducing antiepilepsy drugs. Epilepsy Res 1995; 22: 221–6
Patsalos PN, Duncan JS. New antiepileptic drugs: a review of their current status and clinical potential. CNS Drugs 1994; 2: 40–77
Bebin M, Bleck TP. New anticonvulsant drugs: focus on flunarizine, fosphenytoin, midazolam and stiripentol. Drugs 1994; 48: 153–71
Leach JP, Brodie MJ. New antiepileptic drugs: an explosion of activity. Seizure 1995; 4: 5–17
Leppik IE, Dreifuss FE, Pledger GW, et al. Felbamate for partial seizures: results of a controlled clinical trial. Neurology 1991; 41: 1785–9
Morris JC, Dodson WE, Hatlelid JM, et al. Phenytoin and carbamazepine, alone and in combination: anticonvulsant and neurotoxic effects. Neurology 1987; 37: 1111–8
Porter RJ. How to use antiepileptic drugs. In: Levy RH, Mattson RH, Meldrum BS, editors. Antiepileptic drugs. New York: Raven Press, 1995: 137–48
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Rambeck, B., Specht, U. & Wolf, P. Pharmacokinetic Interactions of the New Antiepileptic Drugs. Clin-Pharmacokinet 31, 309–324 (1996). https://doi.org/10.2165/00003088-199631040-00006
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DOI: https://doi.org/10.2165/00003088-199631040-00006