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Epilepsy is a common neurological disorder that affects more than 50 million people worldwide . It is a chronic condition that is characterized by recurrent spontaneous seizures, which can vary from mild muscle spasms to severe convulsions. These seizures are triggered by irregular and excessive neuronal activity within the brain. They are classed as either partial (localised in a part of the brain) or generalised (distributed). In most cases, epilepsy can be effectively controlled with drugs known as anticonvulsants. An anticonvulsant acts by suppressing the rapid and excessive discharges from the neurons that start seizures. Nonetheless, up to 30% of sufferers will fail to respond to anticonvulsant monotherapy, so will therefore require a combination of antiepileptic drugs . Gabapentin is a relatively new anticonvulsant that is commonly used as add-on therapy for people with drug-resistant partial epilepsy. This essay will focus on both the preclinical and clinical development of gabapentin.
Gabapentin, also known by its brand name Neurontin, was developed and launched by the pharmaceutical company Pfizer Inc. Prior to the making of gabapentin; there were a number of anticonvulsants available on the market already, such as carbamazepine and phenytoin. However, both drugs were known to induce many side-effects in patients, therefore Pfizer decided to develop a new anticonvulsant with fewer adverse effects.
The gabapentin molecule was designed using the structural template of γ-aminobutyric acid (GABA), the main inhibitory neurotransmitter in the central nervous system (CNS) known to be important in the regulation of neuronal excitability. The initial idea was to develop a drug molecule that could freely penetrate the blood-brain barrier and access the CNS in order to control the overexcited neurones. A slight modification in the GABA structure, where the third carbon atom was incorporated into a cyclohexane ring (fig 1), produced a compound that could successfully pass through. The new compound was more lipophilic than GABA - termed gabapentin.
Figure 1. The Structures of Gabapentin and GABA .gabapentin structure.bmp
This increase in lipophilicity was shown by its Log P value (-1.10) at pH 7.4, which was greater than GABA's and closer to the optimal Log P value (2.50) needed for penetration of the blood-brain barrier . However, this new property was not the main reason for gabapentin's ability to pass through the barrier. It was the introduction of the cyclohexane ring into the structure that was largely responsible. The structural difference gave gabapentin properties similar to that of an amino acid. The cyclohexane ring forced the molecule into a folded conformation that is recognised by the L system amino acid transporter. This transporter allows for the entry of amino acids into the CNS, and in this case gabapentin too.
The antiepileptic mechanism of action of gabapentin is currently unknown. Even though it is structurally similar to GABA, many studies have strongly suggested that gabapentin does not interact with the same GABA receptors (GABAA or GABAB). Instead, gabapentin binds specifically with a high affinity to the auxiliary α2δ subunit of voltage-gated calcium channels within the brain. It is already known that this binding is needed for the analgesic activity of gabapentin, but in addition it is believed that the blockage of these calcium channels could also be the reason for the antiepileptic activity of the drug . However, this is not certain and requires further study. Other possible mechanisms by which gabapentin may exert its effect have been suggested. For example, one study has proposed that gabapentin may act to modulate the GAT1 GABA transporter function; whereas other studies have us believe gabapentin is capable of inhibiting GABA-transaminase and activating glutamic acid decarboxylase resulting in increased GABA levels . None as yet have been fully accepted by the scientific community as the definite antiepileptic mechanism of action of gabapentin.
The pharmacokinetic profile of gabapentin was determined following the animal models and clinical trials. Gabapentin was shown to have an attractive pharmacokinetic profile, making it a very useful drug. It is water soluble and rapidly absorbed. The absolute bioavailability of gabapentin in both capsule and solution form is approximately 60% for 900 mg/day dose. The bioavailability is not dose proportional, in fact as the dose increases the bioavailability decreases . Gabapentin is not found bound to plasma proteins, meaning that the drug has a high volume of distribution, with a greater concentration more likely to be present in tissue than in plasma. It is not metabolized in humans therefore it is eliminated from the body by renal excretion as an unchanged drug. The elimination half-life is about 5-7 hours. Gabapentin also has no effect on the metabolism of other antiepileptic drugs, making it valuable in combination therapy.
Gabapentin was initially developed for the treatment of epilepsy. The antiepileptic activity of the drug was first examined in preclinical tests on animal models, before trials were carried out on humans. Gabapentin demonstrated activity against a variety of seizures in mice and rats in maximal electroshock models with doses lower or comparable to those of carbamazepine and phenytoin . The drug also prevented seizures in animals with genetic epilepsy. It was active when it was administered both orally and intravenously. A lethal dose was not identified in mice or rats receiving doses as high as 8000 mg/kg via oral administration. The results from the animal models determined that gabapentin definitely had a positive outcome in animals and was safe enough to be tested in humans as add-on therapy.
During clinical trials, the effects of gabapentin were deemed successful in patients who experienced a 50% or greater reduction in seizure frequency in the treatment period, when compared to the baseline period measured prior to treatment. The proportion of patients that had this reduction was called the 'responder rate.' Adverse effects of the drug were also recorded, with a few patients having to withdraw from treatment as a result. Placebo and gabapentin doses were administered to patients in the trials in identical capsules. The trials were sponsored by Parke Davis (branch of Pfizer), as part of their pre-licensing development procedure for gabapentin .
The first clinical trial (Phase I) testing gabapentin's antiepileptic properties in add-on therapy was carried out by Crawford et al. in 1987 . 25 patients with severe epilepsy (minimum of 1 seizure per week), and had drug-resistance to other anticonvulsants were admitted to study. Patients in this trial suffered from all types of seizures, including partial seizures. All patients were evaluated for two months to determine a baseline seizure frequency, during which the subjects received one or two standard antiepileptic drugs. Following this, the patients were given doses of 300 mg, 600 mg, or 900 mg/day of gabapentin in a double blind cross-over trial design. The therapy they were already on was maintained. Each patient took each dose of gabapentin for two months, a period in which their seizure frequency was again assessed. Four of the subjects were excluded from the published results for various reasons. The results showed that a reduction of 50% or more in seizure frequency was experienced in 43% of patients when on 900 mg/day, 33% on 600 mg/day and 14% on 300 mg/day. However, it is interesting to note that there was no placebo treatment present in this trial. Without a control, it is difficult to compare the full extent of the effect of gabapentin. Nevertheless, the safety and tolerability of the drug were determined from this trial. The most common adverse effects recorded included drowsiness and tiredness.
In 1990, the U.K. Gabapentin Study Group carried out the next clinical trial (Phase II) to further investigate the efficacy of gabapentin . This trial tested 127 patients in a double-blind placebo-controlled design. The patients admitted had partial epilepsy showing at least one partial seizure per week, and were resistant to therapy with one or two standard anticonvulsants. They were followed for three months to establish a baseline seizure frequency. Patients were then randomized and received either placebo or 1200 mg/day for a 14 week treatment phase. All subjects maintained their pre-existing therapy throughout the trial. Of the 61 patients taking 1200 mg/day of gabapentin, the responder rate (50% or more decrease in frequency of partial seizures) was 25%. Comparing this to the 9.8% responder rate of the 66 other patients on placebo, showed that gabapentin definitely had a positive antiepileptic effect. Adverse effects were experienced in thirty-six patients on gabapentin with the most common being somnolence and fatigue once again. These symptoms were only rated as mild however, and were temporary.
In 1993, the U.S. Gabapentin Study Group carried out a trial with 306 patients (Phase III) . This was also a randomized double-blind placebo-controlled trial. All patients were known to be resistant to standard anticonvulsants, and suffered from at least 4 partial seizures per month. A 12 week baseline period was followed by a 12 week treatment period, where the patients were randomized and given either placebo, 600 mg/day, 1200 mg/day or 1800 mg/day of gabapentin. A 50% reduction in seizure frequency was observed in 26.5% of patients on 1800 mg/day, 17.6% of patients on 1200 mg/day and 18.3% on 600 mg/day. The responder rate in the placebo group was 8.5%. The trial showed that higher doses of gabapentin had a greater outcome on the seizure frequency. Adverse effects of the gabapentin included somnolence, dizziness and ataxia, though the symptoms cleared within two weeks.
In 1994 (post marketing), the International Gabapentin Study Group (Anhut et al) followed up with another study of gabapentin efficacy on 272 patients suffering from drug resistant partial epilepsy . The trial was carried out in the same manner as the US Gabapentin study, with a 12 week baseline period and a 12 week treatment period. Subjects then randomly received placebo, 900 mg/day or 1200 mg/day of gabapentin. Twenty-seven patients were excluded from the published results for various reasons. Results showed that 27% of the group on 1200 mg/day experienced a reduction of 50% or more in seizure frequency, whereas 22% of patients on 900 mg/day showed the same effect. The responder rate in the placebo group was 10.1%. This trial served to back up the evidence in previous trials that a higher dosage had a greater effect. The most common adverse effects from this trial were somnolence, dizziness and fatigue. However most of these symptoms were rated as mild.
Total Number of Patients
Dosage in mg/day
Responder Rate in % of patients
Crawford et al. (1987)
U.K. Gabapentin Group (1990)
U.S. Gabapentin Group (1993)
International Gabapentin Group (1994)
Figure 2. Summary of Most Important Clinical Trials Data for Gabapentin as Add-on Therapy for the Treatment of Epilepsy.
Results from the clinical trials proved that gabapentin had a positive antiepileptic effect as add-on therapy for people with drug-resistant partial epilepsy. Pfizer licensed and marketed gabapentin ('Neurontin') in 1993 as an anticonvulsant for add-on treatment. Although initially developed to treat epilepsy, it became apparent after gabapentin was marketed that it induced some other beneficial therapeutic effects too . In particular, the drug showed positive action against chronic neuropathic pain. Further studies by University of Michigan in 1997 proved that gabapentin significantly decreased pain in patients suffering from postherpetic neuralgia . Gabapentin was also tested to see how effective it was in monotherapy treatment of epilepsy. A study by the International Gabapentin Study Group in 1997 compared blind doses of gabapentin to the standard anticonvulsant carbamazepine in open label . On the whole, the results were promising and showed gabapentin to be a potentially useful drug in monotherapy.
Gabapentin has already been proven to be a great success in add-on therapy for sufferers of epilepsy. In addition, the drug has shown to induce fewer and milder side-effects than the likes of carbamazepine and phenytoin. The innovative development of gabapentin was the catalyst in the identification of other drugs like it. Further research into 3-alkylated GABA systems led to the discovery of pregbalin (3-isobutyl GABA), a novel anticonvulsant believed to work in the same fashion as gabapentin. As yet, the mechanism of action of gabapentin is still uncertain. Future studies revealing greater insight into the system by which gabapentin works could be key to furthering our knowledge in neurobiology and the treatment of seizures.
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