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Gabapentin is an antiepileptic drug with an unknown mechanism of action apparently dissimilar to that of other antiepileptic agents, and possessing some desirable pharmacokinetic traits. The drug is not protein bound, is not metabolised and does not induce liver enzymes, diminishing the likelihood of drug interactions with other antiepileptic agents and drugs such as oral contraceptives. Although gabapentin is a structural analogue of the neurotransmitter γ-aminobutyric acid (GABA), which does not cross the blood-brain barrier, gabapentin penetrates into the CNS and its activity is seemingly distinct from GABA-related effects.
Present clinical evaluation is largely restricted to proof of efficacy trials of gabapentin as addon therapy in patients with partial epilepsy resistant to conventional treatment. Gabapentin (usually 600 to 1800 mg/day) provides notable benefit, reducing seizure frequency by ⩾ 50% in 18 to 28% of patients with refractory partial seizures, as shown in 3 double-blind, placebo-controlled trials. Overall, seizure frequency decreased by 18 to 32% during 3-month treatment periods. Patients with complex partial seizures, and partial seizures secondarily generalised, are particularly likely to respond to gabapentin. Current experience with the drug in other seizure types, and as monotherapy, is limited.
Mild adverse events, commonly somnolence, fatigue, ataxia and dizziness, have been reported in about 75% of gabapentin recipients. While the drug has been well tolerated when administered to a few patients for periods of up to 5 years, its long term tolerability profile has yet to be fully expounded.
Thus, with its favourable pharmacokinetic profile, and efficacy in some refractory patients, gabapentin is poised to fill a niche as an adjunct to the treatment of partial epilepsy. Promising results obtained thus far warrant further work to clarify its long term tolerability, its possible efficacy in other seizure types, its position relative to other agents and its use as monotherapy. In the meantime, gabapentin is likely to provide a much-needed option in a therapeutic area requiring complex management.
Gabapentin is active in many standard animal seizure models, protecting against convulsions induced by chemicals (e.g. picrotoxin, bicuculline, strychnine), and some non-chemical stimuli (e.g. audiogenic, maximal electroshock). The profile of its anticonvulsant activity in animal studies thus predicts its clinical efficacy in patients with partial seizures and secondarily generalised tonic-clonic seizures.
Despite its structural similarity to γ-aminobutyric acid (GABA), gabapentin apparently does not act via mechanisms related to this neurotransmitter, but most probably by events modulated through its interaction with a receptor thought to be associated with the L-system amino acid carrier protein.
Sedative effects have occurred in rodents given gabapentin ⩾400 mg/kg (orally or intragastrically). There is some evidence of slight improvement in psychomotor function in healthy volunteers who received one dose of gabapentin 200mg, and there have been spontaneous reports of improved memory and perception in a few patients.
Mean maximum plasma gabapentin concentrations are attained 2 to 3 hours after a single oral 300mg dose, and measured 2.7 to 2.99 mg/L in healthy volunteers. Absorption kinetics of gabapentin are dose-dependent, rather than dose-proportional, possibly due to a saturable transport system. Thus, bioavailability of a single 300mg oral dose of gabapentin is 60%, but decreases with increasing dose.
As demonstrated in rats, gabapentin is extensively distributed in body tissues, concentrating particularly in pancreas and kidney. Unlike GABA, gabapentin has some lipophilicity and readily crosses the blood-brain barrier, producing a CSF: plasma concentration ratio of 0.09 to 0.14 as measured in 5 patients. Its volume of distribution is large, estimated as 50 to 60L in healthy volunteers. The drug is not bound to human plasma proteins.
Elimination of gabapentin is wholly accountable by renal clearance, in contrast to many antiepileptic drugs which are metabolised. The elimination half-life of gabapentin is about 5 to 7 hours after a single oral dose of 200 to 400mg. As expected, renal impairment reduces drug clearance and augments plasma gabapentin concentrations in a linear fashion.
A dose-response pattern is apparent for plasma gabapentin concentrations and for clinical effect within the dosage range 600 to 1800 mg/day. However, monitoring of plasma gabapentin concentrations is unnecessary, and dosage of gabapentin should be adjusted according to clinical response.
Concomitant administration of gabapentin does not influence the pharmacokinetics of conventional antiepileptic drugs [valproic acid, phenobarbital (phenobarbitone), carbamazepine or phenytoin] and oral contraceptives, nor are the pharmacokinetics of gabapentin modified by antiepileptic drugs. This potentially advantageous property of gabapentin is attributable to its lack of protein binding, absence of metabolic clearance, and inability to induce liver enzyme activity.
Several placebo-controlled proof of efficacy trials have confirmed the benefit of gabapentin as add-on therapy in some patients with partial seizures resistant to conventional treatment. Approximately 18 to 28% of patients with refractory seizures in these trials experienced reductions in seizure frequency of at least 50% during 3 months’ treatment with gabapentin 600 to 1800mg daily, versus 8.4 to 10% in placebo groups. Overall seizure frequency decreased by approximately 18 to 32% with gabapentin, and increases in seizure frequency occurred in almost twice as many placebo recipients (38 to 49%) as gabapentin recipients (19 to 33%). Response ratio values and global evaluations by patient and physician strengthen the evidence for a beneficial effect of gabapentin. Complex partial seizures and partial seizures with secondary generalisation seem particularly amenable to gabapentin therapy.
Over longer term gabapentin administration (⩽2400 mg/day usually for up to 2 years but as long as 5 years in a few patients) in noncomparative trials, approximately 70% of patients showed some improvement in seizure control, 25 to 50% exhibited decreases in seizure frequency of ⩾50%, and 20 to 30% remained unchanged or experienced more frequent seizures. An overall responder rate of 36% at 84 days was recorded among 400 patients treated with gabapentin for ⩽5 years. Early indications of benefit with gabapentin as monotherapy await confirmation, as does its efficacy relative to other antiepileptic drugs.
Somnolence (20%), dizziness (18%) ataxia (13%) and fatigue (11%) are the most common adverse events observed during gabapentin therapy, as reported in 1748 patients, whereas in placebo groups somnolence (9.8%), headache (9%), dizziness (7.8%) and nausea/vomiting (7.5%) were most frequent. These and other symptoms have usually been mild, abating with continued gabapentin therapy, but have led to treatment withdrawal in 7% of patients in premarketing trials. The overall proportion of patients reporting adverse events during gabapentin administration has been calculated to be about 75%, versus 55% for placebo.
No changes in haematological or other laboratory test results have been observed with gabapentin therapy, other than isolated cases of reduced white blood cell count possibly also related to concomitant carbamazepine therapy. The clinical significance, if any, of the development of pancreatic carcinoma in male rats administered very high doses of gabapentin for 2 years remains unclear.
The long term tolerability of gabapentin has not been described in detail as yet. Confirmation is required of current data suggesting that gabapentin is well tolerated during extended treatment periods.
Dosage and Administration
A dosage range of gabapentin 600 to 1800mg daily, divided into 3 doses given every 8 hours, has been used most often as add-on therapy in patients with refractory partial seizures in clinical trials. Dosage should be titrated to response. Dosage reduction is necessary in patients with impaired renal function. Gabapentin withdrawal, or addition of other antiepileptic drugs, should be performed slowly to avoid rebound seizures.
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- Abou-Khalil B, McLean M, Castro O, Courville K. Gabapentin in the treatment of refractory partial seizures. Abstract. Epilepsia 31: 644, 1990Google Scholar
- Abou-Khalil B, Shellenberger MK, Anhut H. Two open-label multicenter studies of the safety and efficacy of gabapentin in patients with refractory epilepsy. Abstract. Epilepsia 33 (Suppl. 3): 77, 1992Google Scholar
- Allen E, Jawad S, Wrae S, Richens A, Does the anticonvulsant gabapentin lack enzyme inducing properties? Abstract. 17th International Epilepsy Congress, Jerusalem, 1987Google Scholar
- Anhut H, Leppik I, Schmidt B, Thomann P. Drug interaction study of the new anticonvulsant gabapentin with phenytoin in epileptic patients. Abstract. Naunyn-Schmiedeberg’s Archives of Pharmacology 337 (Suppl.): R127, 1988Google Scholar
- Anon. Gabapentin prescribing information, USA, 1993Google Scholar
- Bartoszyk GD. Gabapentin and convulsions provoked by excitatory amino acids. Naunyn-Schmiedeberg’s Archives of Pharmacology 324 (Suppl.): R24, 1983Google Scholar
- Bartoszyk GD, Meyerson N, Reimann W, Satzinger G, von Hodenberg A. New anticonvulsant drugs. Gabapentin. In Meldrum BS and Porter RJ (Eds) Current problems in epilepsy, Vol.4, pp. 147–163, John Libbey, London, 1986Google Scholar
- Bauer G, Bechinger D, Castell M, Deisenhammer E, Egli M, et al. Gabapentin in the treatment of drug-resistant epileptic patients. Advances in Epileptology 17: 219–221, 1989Google Scholar
- Browne T. Efficacy and safety of gabapentin. In Chadwick D (Ed.) New trends in epilepsy management: the role of gabapentin. pp. 47–58, Royal Society of Medicine Services, London, 1993Google Scholar
- Boyd RA, Brockbrader HN, Türck D, Sedman AJ, Posvar EL, et al. Effect of subject age on the single dose pharmacokinetics of orally administered gabapentin (CI-945). Abstract. Pharmaceutical Research 7 (Suppl.): S215, 1990Google Scholar
- Bruni J, Saunders M, Anhut H, Sauermann W. Efficacy and safety of gabapentin (Neurontin): a multicenter, placebo-controlled, double-blind study. Abstract. Neurology 41 (Suppl. 1): 330, 1991Google Scholar
- Busch JA, Radulovic LL, Bockbrader HN, Underwood BA, Sedman AJ, et al. Effect of Maalox TC® on single-dose pharmacokinetics of gabapentin capsules in healthy subjects. Abstract. Pharmaceutical Research 9 (Suppl. 10): S315, 1992Google Scholar
- Comstock TI, Sica DA, Bockbrader HN, Underwood BA, Sedman AJ. Gabapentin pharmacokinetics in subjects with various degrees of renal function. Abstract. Journal of Clinical Pharmacology 30: 862, 1990Google Scholar
- Dodrill CB, Wilensky AJ, Ojemann LM, Temkin NR, Shellenberger K, et al. Neuropsychological, mood, and psychosocial effects of gabapentin. Abstract. Epilepsia 33 (Suppl. 3): 117, 1992Google Scholar
- Fröscher W. Therapy of refractory epilepsy. Zeitschrift für Allgemeinmedizin 65: 478–483, 1989Google Scholar
- Garofalo E, Koto E, Feuerstein T. Experience with gabapentin overdose: five case studies. Presented at the 20th International Epilepsy Congress, July 3-8, 1993Google Scholar
- Graves NM, Leppik IE, Wagner ML, Spencer MM, Erdmann GR. Effect of gabapentin on carbamazepine levels. Abstract. Epilepsia 31: 644–645, 1990Google Scholar
- Graves NM, Holmes GB, Leppik E, Rask C, Slavin M, et al. Pharmacokinetics of gabapentin in patients treated with phenytoin. Abstract. Pharmacotherapy 9: 196, 1989Google Scholar
- Graves NM, Leppik IE. Antiepileptic medications in development. DICP, The Annals of Pharmacotherapy 25: 978–986, 1991Google Scholar
- Haas HL, Wieser H-G. Gabapentin: action on hippocampal slices of the rat and effects in human epileptics. Abstract no. 9. Proceedings of the Golden Jubilee Conference and Northern Europe Epilepsy Meeting, York, Sept 1986Google Scholar
- Halstenson CE, Keane WF, Türck D, Bockbrader HN, Eldon MA, et al. Disposition of gabapentin (GAB) in hemodialysis (HD) patients. Abstract. Journal of Clinical Pharmacology 32: 751, 1992Google Scholar
- Leppik IE, Shellenberger MK, Anhut H. Two open-label multi-center studies of the safety and efficacy of gabapentin as addon therapy in patients with refractory partial seizures. Abstract. Epilepsia 33 (Suppl. 3): 117, 1992Google Scholar
- Leiderman D, Anhut H, Sauermann W, Baron B. Response to gabapentin by type of partial seizure. Presented at the 20th International Epilepsy Congress, Oslo, July 3-8, 1993Google Scholar
- Ojemann LM, Friel PN, Ojemann GA. Gabapentin concentrations in human brain. Abstract. Epilepsia 29: 694, 1988Google Scholar
- Pedley TA. The challenge of intractable epilepsy. In Chadwick D (Ed) New trends in epilepsy management: the role of gabapentin. pp. 59–66, Royal Society of Medicine Services, London, 1993Google Scholar
- Pierce MW, Anhut H, Sauermann W. Gabapentin as an effective treatment for patients with refractory partial seizures. Presented at the 20th International Epilepsy Congress, Oslo, July 3-8, 1993Google Scholar
- Richens A. Clinical pharmacokinetics of gabapentin. In Chadwick D (Ed) New trends in epilepsy management: the role of gabapentin. pp. 41–46, Royal Society of Medicine Services, London, 1993Google Scholar
- Saletu B, Grünberger J, Linzmayer L. Evaluation of encephalotropic and psychotropic properties of gabapentin in man by pharmaco-EEG and psychometry. International Journal of Clinical Pharmacology, Therapy and Toxicology 24: 362–373, 1986Google Scholar
- Schear MJ, Wiener JA, Rowan AJ. Long-term efficacy of gabapentin in the treatment of partial seizures. Abstract. Epilepsia 32 (Suppl. 3): 6, 1991Google Scholar
- Stewart BH, Kugler AR, Thompson PR, Bockbrader HN. A saturable transport mechanism in the intestinal absorption of gabapentin is the underlying cause of the lack of proportionality between increasing dose and drug levels in plasma. Pharmaceutical Research, in press, 1993Google Scholar
- Taylor CP. Mechanism of action of new antiepileptic drugs. In Chadwick D (Ed) New trends in epilepsy management: the role of gabapentin. pp. 13–40, Royal Society of Medicine Services, London, 1993Google Scholar
- US Gabapentin Study Group. Gabapentin as add-on therapy in refractory partial epilepsy: a double-blind, placebo-controlled, parallel-group study. Neurology, in press, 1993Google Scholar
- Vollmer K-O, Anhut H, Thomann P, Wagner F, Jähnchen D. Pharmacokinetic model and absolute bioavailability of the new anticonvulsant gabapentin. Advances in Epileptology 17: 209–211, 1989Google Scholar
- Vollmer K-O, Türck D, Bockbrader HN, Busch JA, Chang T, et al. Summary of Neurotin (gabapentin) clincial pharmacokinetics. Abstract. Epilepsia 33 (Suppl. 3): 77, 1992Google Scholar
- Wilensky AJ, Temkin NR, Ojemann LM, Ricker B, Holubkov A, et al. Gabapentin and carbamazepine as monotherapy and combined: a pilot study. Abstract. Epilepsia 33 (Suppl. 3): 77, 1992Google Scholar