[Medical Sciences Bulletin]

Medical Sciences Bulletin Contents
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Gabapentin Approved for Refractory Epilepsy

Reprinted from the February 1994 issue of Medical Sciences Bulletin,
published by Pharmaceutical Information Associates, Ltd.
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[-]Indication: Refractory partial epilepsy

     [-]Drug Tradename: Neurontin
     [-]Manufacturer: Parke-Davis, division of Warner- Lambert

     [-]Drug Tradename: Dilantin
     [-]Manufacturer: Parke-Davis, division of Warner- Lambert

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Epilepsy is a fairly common neurologic disturbance, affecting about 1% of
the population. A majority of the patients with diagnoses of epilepsy soon
go into remission (about 70%), but for the remainder the condition will
become chronic, and in some of these patients seizures are resistant to
drug therapy. Recently the Food and Drug Administration (FDA) granted
marketing approval for a new antiepileptic agent for use in patients with
therapy-resistant seizures. Gabapentin (Neurontin/Parke-Davis, division of
Warner-Lambert) was approved for "add-on" treatment of partial seizures in
patients whose epilepsy is incompletely controlled by other
anticonvulsants.

Mode of Action

This interesting drug is an analog of the inhibitory neurotransmitter
gamma- aminobutyric acid (GABA) and was initially thought to act via
GABAergic mechanisms. However, researchers found that gabapentin does not
interact with GABA receptors, nor does it interfere with GABA metabolism.
There is some evidence that gabapentin may increase the GABA content of
some brain regions, but the significance of this finding is not known.
Unlike phenytoin or carbamazepine, gabapentin does not interact with sodium
channels, nor does it influence receptors for benzodiazepines, opioids,
catecholamines, or acetylcholine. Instead, gabapentin appears to act by
binding a specific protein found only on neurons in the central nervous
system. This protein, which does not appear to bind any other antiepileptic
drug, is found in highest density in areas of the neocortex that are rich
in synapses containing the excitatory neurotransmitter glutamine.

Clinical Data

Combined data from several short-term clinical trials (five double-blind,
parallel- group studies and two smaller studies) indicate that gabapentin
in doses of 600 to 1800 mg a day is effective for reducing tonic-clonic
seizures and partial complex seizures in patients with refractory epilepsy.
One of these studies -- the multicenter, double-blind United Kingdom
Gabapentin Study -- involved 127 patients with drug- resistant partial
epilepsy. Partial seizures were reduced by at least 50% in one quarter of
patients who received gabapentin add-on therapy, compared with less than
one tenth of patients given placebo. Gabapentin was tolerated well; the
most common side effects were sedation and fatigue. Data from patients
enrolled in longer-term studies -- 650 patients receiving gabapentin for at
least 1 year and 116 patients receiving the drug for more than 4 years --
indicate that tolerance to gabapentinās antiepileptic effects does not
develop. There are no data on efficacy in children or in patients with
generalized epilepsy, although studies are currently under way.

Absorption and Metabolism

Gabapentin is rapidly absorbed orally, with maximum plasma concentrations
reached within 3 hours of administration. Food has no effect on absorption,
so the drug can be given at any time. Gabapentin passes the blood-brain
barrier, does not bind plasma proteins, and is not metabolized; kinetics
are linear at therapeutic doses. Gabapentin is unusual among
anticonvulsants in that it does not interfere with other antiepileptic
drugs. This is because it has a unique mechanism of action, it does not
interact with protein- bound drugs, and it does not appear to induce
hepatic enzymes. Clearance is linearly correlated with creatinine
clearance, so the dosage can be adjusted for patients with renal failure in
accordance with this parameter. Gabapentin has a half-life of 5 to 7 hours,
which means three daily doses are probably necessary, although twice-daily
administration may be adequate. The dosage should be adjusted on the basis
of clinical symptoms and signs as well as seizure response. The lack of
drug interactions and simple pharmacokinetics make gabapentin particularly
suitable for add-on therapy.

Adverse Effects

Gabapentin is tolerated well. Only 7.4% of 1748 patients who received the
drug during clinical trials withdrew because of an adverse effect, compared
with 3.3% of 485 patients who received placebo (in addition to at least one
concurrent antiepileptic drug). Side effects reported most often were
somnolence, dizziness, ataxia, fatigue, nystagmus, headache, and nausea.
Gabapentin does not appear to alter hematologic or biochemical variables,
so routine testing is not necessary. Unlike phenytoin and carbamazepine,
which cause hypersensitivity reactions in 3% to 10% of patients treated,
gabapentin is not associated with idiosyncratic reactions. However, one
interesting effect emerged in animal trials. Male rats treated for 2 years
with high-dose gabapentin (2 g/kg/day) showed a significant increase in
acinar-cell pancreatic tumors. There was no evidence of local or metastatic
spread, and these rats actually survived longer than control animals.
Gabapentin accumulates in rat pancreatic tissue in much higher
concentrations than in human pancreas, so the human carcinogenic potential
is probably low.

In conclusion, gabapentin appears to be a safe alternative for patients
with refractory partial epilepsy. The drug will be priced wholesale at
approximately $2.25/day for the initial 900-mg dose. Phenytoin
(Dilantin/Parke-Davis) is the market leader, accounting for close to half
of the total prescriptions for antiepilepsy drugs. Since Parke-Davis
intends to promote gabapentin as add-on therapy with phenytoin, gabapentin
may reach $100 million in annual sales within 5 years.

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References

Chadwick D. Lancet. 1993; 343: 89-91.

Gabapentin Study Group. Lancet. 1990; 335: 1114-1117.

Additional information from the manufacturer.
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