Pregabalin: ein wirksames neues Zusatzmedikament zur Behandlung fokaler Epilepsien

Zusammenfassung

Pregabalin (S-[+]-3-isobutyl-GABA; PGN, Handelsname Lyrica®) ist ein neues Medikament zur Kombinationstherapie fokaler Epilepsien mit oder ohne sekundär generalisierten tonisch-klonischen Anfällen für Erwachsene, das durch strukturelle Variation des Gamma-Aminobuttersäure-(GABA-)Moleküls zielgerichtet entwickelt wurde. Es liegen umfangreiche, kontrollierte Prüfstudien an fast 1500 Patienten mit fokalen Epilepsien vor. Der Wirkmechanismus beruht auf der Wirkung von PGN als Ligand der präsynaptischen α2δ-Untereinheit des spannungsabhängigen Kalziumkanals. Die Kombinationstherapie mit PGN beginnt mit 150 mg/d, verteilt auf 75-0-75 mg/d. Falls erforderlich, wird die Tagesdosis nach 7 Tagen auf 300 mg gesteigert (150-0-150 mg). Die Maximaldosis beträgt 600 mg/d (300-0-300 mg). Bei der Maximaldosis kommt es bei etwa 15% der Patienten innerhalb von 12 Wochen zu einer Gewichtszunahme von mindestens 7% des Körpergewichtes, deren Langzeitverlauf sicherlich genauerer Beobachtung bedarf. Aufgrund der renalen Ausscheidung von PGN sollte bei einer Kreatinin-Clearance von weniger als 30 ml/min die Dosis gemäß der Fachinformation reduziert werden. PGB wird nahezu komplett unmetabolisiert im Urin ausgeschieden. Das hepatische CytochromP450-abhängige Enzymsystem ist somit nicht involviert. Es kommt nicht zur Wirkungsabnahme oder Nebenwirkungszunahme infolge enzyminduzierter pharmakokinetischer Interaktionen. Zusätzlich hat PGN – wie in kontrollierten Studien an Patienten mit schmerzhafter peripherer Neuropathie und Angsterkrankungen nachgewiesen – anxiolytische und die gestörte Schlafstruktur verbessernde Eigenschaften, was bei der häufigen Komorbidität von Epilepsien und Angsterkrankungen oder Schlafstörungen vorteilhaft sein kann.

Summary

Pregabalin (S-+)-3-isobutyl-GABA; PGN, trade name Lyrica™) is a new antiepileptic drug for add-on treatment of partial seizures with or without secondary generalization for adults of age 18 and older. It was developed through structural variation of gamma-amino-butyric-acid (GABA). PGN has been evaluated in randomized controlled trials in close to 1500 patients with partial epilepsy. The mechanism of action involves action of PGN as a ligand of the presynaptic α2δ subunit of voltagegated calcium channel. Add-on treatment with PGN starts with 150 mg/day (75-0-75 mg). If needed, the daily dose can be increased to 300 mg (150-0-150 mg) after 7 days. The maximal daily dose is 600 mg (300-0-300 mg). During the 12-week treatment with 600 mg weight gain (≥ 7% of bodyweight) is seen in 15% of patients. The long-term course of this adverse event needs to be monitored carefully. Because of the renal excretion of PGN the daily dose needs to be lowered (see package insert) in patients with a creatinin clearance of less than 30 ml/min. PGN is excreted nearly fully unmetabolized in urine. The hepatic cytochrome-450 dependent enzyme system is not involved. This explains why PGN does not require titration and is easy to combine with other antiepileptic drugs or other medication without impaired efficacy or increased toxicity due to enzyme inducing pharmacokinetic drug interactions. In addition, PGN has shown in controlled trials in patients with peripheral neuropathic pain or anxiety disorders anxiolytic properties and restores impaired sleep structures which may be useful considering the frequent comorbidity of epilepsy and anxiety disorders and insomnia.

Schlüsselwörter

Pregabalin - Epilepsie - Epilepsietherapie - Antiepileptika - fokale Anfälle

Keywords

Pregabalin - epilepsy - treatment of epilepsy - antiepileptic drugs - partial seizures

• Literatur

• 1 Abou-Khalil BW, Vazquez BR, Beydoun A. et al. Pregabalin in patient monotherapy trial: A double-blind, low-dose active-controlled, multicenter study in patients with refractory partial epilepsy (protocol 1008-007). Neurology 1999; 52 6 SUPPL. 2 A390.
• 2 Arroyo S, Anhut H, Kugler AR. et al. Pregabalin add-on Treatment: A randomized, doubleblind, placebo-controlled, dose-response-study in adults with partial seizures. Epilepsia 2004; 45 (01) 20-7.
• 3 Beydoun AA, Uthman BM, Ramsay RE. et al. Pregabalin add-on trial: double-blind, multicenter study in patients with partial epilepsy. Epilepsia 2000; 41 (Suppl. 07) 253-4.
• 4 Beydoun A, Kugler A, Greiner M. et al. Safety and sustained long-term efficacy of pregabalin for partial-onset seizures. Epilepsia 2003; 44 (Suppl. 09) 258-9.
• 5 Bockbrader HN, Burger PJ, Corrigan BW. et al. Population pharmacokinetic (PK) analyses of pregabalin (PGB) in adult patients with refractory partial seizures. Epilepsia 2001; 42 (Suppl. 07) 84.
• 6 Bockbrader HN, Strand JC, Wesche DL. et al. Drug-interaction studies of pregabalin (CI1008, PGB) in patients with epilepsy maintained on either valproate (VPA), lamotrigine (LTG), phenytoin (PHT), or carbamazepine (CBZ). Epilepsia 2001; 02 (Suppl. 07) 86-7.
• 7 Brodie MJ, Mohanraj R. Response to treatment in newly diagnosed epilepsy. Epilepsia 2003; 44 (Suppl. 09) 14.
• 8 Bryans JS, Wustrow DJ. 3-Substituted GABA analogs with central nervous system activity: a review. Medical Research Review 1999; 19: 149-177.
• 9 Dworkin RH, Corbin AE, Young Jr JP. et al. Pregabalin for the treatment of postherpetic neuralgia: A randomized, placebo-controlled trial. Neurology 2003; 60 (08) 1274-83.
• 10 Elger Ch, Roder B, Bockbrader H. et al. Pregabalin in-patient monotherapy trial. Epilepsia 1999; 40 (Suppl. 02) 247.
• 11 Fachinformation Pregabalin (Lyrica) 2004. Anhang 1. Zusammenfassende Merkmale des Arzneimittels (Pfizer-Dokumentation).
• 12 Fink K, Dooley DJ, Wolfgang MP. et al. Inhibition of neuronal Ca2+ influx by gabapentin and pregabalin in the human neocortex. Neuropharmacology 2002; 42 (02) 229-36.
• 13 French J. Pregabalin: what are the prospects of this newest AED?. Epilepsia 2004; 45 (Suppl. 03) 211.
• 14 French JA, Kugler AR, Robbins JL, Knapp LE, Garofalo EA. Dose-response trial of pregabalin adjunctive therapy in patients with partial seizures. Neurology 2003; 60 (10) 1631-37.
• 15 French JA, Kugler AR, Lee CM, Greiner MJ, Knapp LE. Pregabalin efficacy is not a function of epilepsy severity. Neurology 2003; 60 (Suppl. 01) A473.
• 16 Greiner MJ, Kugler AR, Lee CM, Knapp LE, Garofalo EA. Pregabalin shows efficacy in reducing simple partial, complex partial, and secondarily generalized seizures. Epilepsia 2003; 44 (Suppl. 09) 260.
• 17 Huppertz HJ, Feuerstein TJ, Schulze-Bonhage A. Myoclonus in epilepsy patients with anticonvulsive add-on therapy with pregabalin. Epilepsia 2001; 42 (06) 790-2.
• 18 Kugler AR, French JA, Lee CM, Greiner MJ, Knapp LE. No evidence of pharmacodynamic interaction with pregabalin. Neurology 2003; 60 (Suppl. 01) A474.
• 19 Miller R, Frame B, Corrigan B. et al. Exposureresponse analysis of pregabalin add-on treatment of patients with refractory partial seizures. Clinical Pharmacology & Therapeutics 2003; 73 (06) 491-505.
• 20 Pande AC, Crockatt JG, Feltner DE. et al. Pregabalin in generalized anxiety disorders: a placebo-controlled trial. Am J Psychiatry 2003; 160: 533-40.
• 21 Perucca E, Kugler A, Greiner M, Robbins J. Pregabalin demonstrates anticonvulsant activity onset by second day. Neurology 2003; 60 (Suppl. 01) A145.
• 22 Ramsay RE, Kugler AR, Anhut H. et al. Pregabalin adjunctive therapy in patients with partial seizures. Epilepsia 2001; 42 (Suppl. 07) 211.
• 23 Randinitis EJ, Posvar EL, Alvey CW. et al. Pharmacokinetics of pregabalin in subjects with various degrees of renal function. Journal of Clinical Pharmacology 2003; 43 (03) 277-83.
• 24 Sabatowski R, Galvez R, Cherry DA. et al. The 1008-045 Study Group: Pregabalin reduces pain and improves sleep and mood disturbances in patients with post-herpetic neuralgia: results of a randomised, placebo-controlled clinical trial. Pain 2004; 109 1-2: 26-35.
• 25 Schmidt D. The clinical impact of new antiepileptic drugs after a decade of use in epilepsy. Epilepsy Research 2002; 50: 21-32.
• 26 Uthman BM, Beydoun A, Kugler AR. et al. Long-term efficacy and tolerability of pregabalin in patients with partial seizures. Epilepsia 2002; 43 (Suppl. 07) 240.
• 27 Vazquez B, Abou-Khalil B, Biton V. et al. Pregabalin monotherapy in hospitalized patients a study design for early demonstration of anticonvulsant efficacy. Epilepsia 1998; 39 (Suppl. 06) 67-8.
• 28 Vega M, McJilton J, Ramsay RE. et al. Efficacy and safety of long term treatment of refractory epilepsy with pregabalin. Epilepsia 2000; 41 (Suppl. 07) 88-9.