, Volume 55, Issue 3, pp 437–460 | Cite as


A Review of its Pharmacodynamic and Pharmacokinetic Properties and Therapeutic Potential in the Management of Epilepsy
  • Julie C. Adkins
  • Stuart Noble
Adis Drug Evaluation



Tiagabine is a γ-aminobutyric acid (GABA) uptake inhibitor which is structurally related to nipecotic acid but has an improved ability to cross the blood-brain barrier. Clinical trials have shown that tiagabine is effective as add-on therapy in the management of patients with refractory partial epilepsy. In short term studies of this indication, tiagabine ≤ 64 mg/day for 7 to 12 weeks reduced the complex partial and simple partial seizure frequency by ≥ 50% in 8 to 31 and 28.2 to 37% of patients, respectively. Tiagabine appeared to produce a sustained reduction in seizure frequency in studies of up to 12 months’ duration.

Data from preliminary studies are currently insufficient to confirm the usefulness of tiagabine when used as monotherapy or in the treatment of children with epilepsy. Further studies are, therefore, necessary to more fully elucidate the efficacy of the drug in these settings.

Adverse events associated with tiagabine are primarily CNS-related and include dizziness, asthenia, nonspecific nervousness and tremor. Skin rash or psychosis occurred with similar frequencies among tiagabine- and placebo-treated patients. With long term administration (≥ 1 year for many patients), the profile and incidence of adverse events was similar to that for short term therapy.

Tiagabine does not appear to affect the hepatic metabolism of other drugs such as carbamazepine and phenytoin. Possible disadvantages of tiagabine include its short plasma elimination half-life, necessitating 2 to 4 times daily administration, and its inducible hepatic metabolism.

Thus, tiagabine is a new antiepileptic agent with a novel mechanism of action, which has demonstrated efficacy in the adjunctive treatment of patients with refractory partial epilepsy. Further investigation of the efficacy of tiagabine is expected to provide a clearer definition of its place in the treatment of epilepsy and its relative merits in relation to other antiepileptic drugs.

Pharmacodynamic Properties

Tiagabine increases synaptosomal concentrations of the inhibitory neurotransmitter γ-aminobutyric acid (GABA) via inhibition of the GABA transporter GAT-1. The increase in synaptic concentrations of GABA leads to potentiation of GABA-mediated inhibitory neurotransmission. Tiagabine lacks appreciable affinity for other receptor or uptake sites including benzodiazepine, histamine H1, serotonin 5-HT1B or dopamine D1 or D2 receptors or β1− or β2−adrenoceptors. It is not a substrate for the GABA uptake carrier and is therefore unlikely to act as a false transmitter.

Tiagabine is active in a number of animal seizure models, protecting against seizures induced by chemical [e.g. methyl-6,7-dimethoxy-4-ethyl-β-carboline-3-carboxylate (DMCM) and pentylenetetrazol (PTZ)] and nonchemical stimuli (e.g. audiogenic and kindling). It is a more potent anticonvulsant than the conventional antiepileptics phenytoin, phenobarbital, carbamazepine and valproic acid against audiogenic and DMCM- and PTZ-induced tonic or clonic seizures in mice and rats. Tiagabine is also more potent than lamotrigine, gabapentin and vigabatrin in protecting against audiogenic and DMCM- and PTZ-induced tonic or clonic seizures in mice and was the only drug able to block PTZ-induced clonic seizures in mice. Tiagabine may be proconvulsant in animal models of non-convulsive epilepsy.

Results from short and long term studies in patients with epilepsy have revealed no clinically significant deterioration in cognitive performance or electroencephalographic changes during tiagabine therapy and suggest that the drug may even have a slight beneficial effect on cognition under certain circumstances.

Pharmacokinetic Properties

Tiagabine is well absorbed after oral administration and has an absolute oral bioavailability of 90%. Peak plasma concentrations occurred approximately 1 hour after administration and measured 43 to 552 μg/L in healthy volunteers after single-dose administration of tiagabine 2 to 24mg. Multiple-dose administration of tiagabine does not result in significant drug accumulation. The rate, but not the extent, of absorption of tiagabine is decreased by concomitant food intake. Tiagabine is widely distributed throughout the body (volume of distribution is approximately 1 L/kg) and approximately 96% of the drug in human plasma is bound to plasma proteins.

Tiagabine is extensively metabolised by the hepatic cytochrome P450 enzyme CYP3A. 63% of a radiolabelled orally administered dose was excreted in the faeces and 25% in the urine. The plasma clearance of tiagabine is 21.4 L/h in patients receiving concomitant enzyme-inducing antiepileptic drugs such as carbamazepine, phenytoin and primidone and 12.8 L/h in patients with epilepsy not receiving concomitant treatment with these agents. The elimination half-life of tiagabine ranges from 3.8 to 9 hours in patients with epilepsy; patients receiving concomitant treatment with enzyme-inducing antiepileptic drug therapy exhibit values at the lower end of this range. Conversely, the clearance of tiagabine is reduced in patients with hepatic impairment, which may necessitate dosage reduction. Renal impairment or old age do not appear to significantly reduce the clearance of tiagabine; however, clearance of the drug appears to be slightly increased in children.

Although there is some evidence to suggest a relationship between tiagabine plasma concentration and therapeutic effect, there are currently insufficient data to recommend routine monitoring of plasma tiagabine concentrations in patients receiving the drug.

Concomitant administration of tiagabine has been shown not to influence the pharmacokinetics of conventional antiepileptic drugs such as carbamazepine and phenytoin or other drugs including oral contraceptives, theophylline, warfarin and digoxin. A significant decrease (approximately 10 to 12%) in the peak plasma concentration and area under the plasma concentration-time curve for valproic acid has been reported in patients receiving concomitant tiagabine therapy; however, because valproic acid has a wide therapeutic range (50 to 100 mg/L), thisdecrease was considered to be of limited clinical significance.

Therapeutic Efficacy

The results of 5 double-blind placebo-controlled studies (2 crossover and 3 parallel-group studies) have shown tiagabine ≤64 mg/day to be effective as add-on therapy in patients with refractory partial epilepsy. According to a pooled analysis of these studies, 23% of patients treated with tiagabine, compared with 9% of placebo-treated patients, experienced a reduction in total seizure frequency of at least 50% during 7 to 12 weeks of treatment. The reduction in 4-week overall seizure frequency (25 vs 0.1%) and increase in the number of seizure-free days(6 vs 0%) were significantly greater for tiagabine than for placebo recipients. Individual results from 3 of these studies showed a ≥50% decrease in seizure rate relative to baseline in 8 to 31% and 28.2 to 37% of patients with complex partial and simple partial seizures, respectively. A corresponding response rate of 63% was reported for patients who experienced secondarily generalised tonic-clonic seizures in 1 study.

The clinical benefits of adjunctive tiagabine therapy appear to be maintained during long term treatment. Approximately 30 to 40% of patients treated with tiagabine ≤80 mg/day for up to 12 months in nonblind extension studies continued to experience a ≥50% reduction in overall seizure frequency.

Initial studies have reported a beneficial effect with tiagabine monotherapy in some patients with epilepsy refractory to monotherapy with other antiepileptic drugs. Among 31 patients recruited to a dose-ranging study, 19 were converted to tiagabine monotherapy for ≥2 weeks and 12 of these patients completed the study at a mean dosage of 38.4 mg/day. In a second study, efficacy rates (≥50% reduction in complex partial seizure frequency from baseline) were 31 and 18%, respectively, after treatment with tiagabine 36 and 6 mg/day (intent-to-treat analysis). Notably, both studies reported a high rate of study withdrawal (>50%); this was not an unexpected finding, as the refractory nature of the disease in patients recruited to these studies made successful conversion to tiagabine monotherapy less likely.

The few data available from the only comparative study of tiagabine monotherapy (vs carbamazepine monotherapy) in patients with newly diagnosed partial epilepsy do not allow an accurate assessment of efficacy. Studies are therefore required to establish the efficacy of tiagabine in relation to conventional and newer antiepileptic agents.

In small noncomparative studies, tiagabine (0.25 to 1.5 mg/kg/day or 32 to 80 mg/day) also demonstrated efficacy as add-on therapy in children and adolescents (aged 2 to 16 years) with refractory partial epilepsy, producing a >50% reduction in partial seizure frequency in approximately 20 to 50% of patients.


The most frequent adverse events in 675 patients with refractory epilepsy treated with tiagabine as add-on therapy (typically ≤64 mg/day for up to 12 weeks) were dizziness (30%), asthenia (24%), nonspecific nervousness (12%) and tremor (9%) [pooled data from placebo-controlled studies]. This compared with a significantly lower incidence of 13, 12, 3 and 3%, respectively, among placebo recipients (n = 363). Diarrhoea, depressed mood and emotional lability were also significantly more frequent with tiagabine (4 to 7% vs 1 to 2%). Other adverse events, including psychosis and skin rash which are frequently associated with other antiepileptic drugs, occurred with a similar frequency among tiagabine- and placebo-treated patients. These and other symptoms were generally mild or moderate and occurred early in the course of therapy. Treatment discontinuation due to adverse effects has been reported in 15% of patients treated with adjunctive tiagabine therapy and 33% of patients treated with tiagabine monotherapy.

Longer term tolerability data (including results from 814 patients treated with tiagabine for ≥1 year), suggest that the profile and incidence of adverse effects associated with long term tiagabine therapy are similar to those reported during short term therapy.

Clinically significant changes in haematological or liver function tests have not been observed during tiagabine therapy. Furthermore, the risk of status epilepticus appears to be minimal and similar to that reported for patients with epilepsy not treated with tiagabine.

Dosage and Administration

Dosage recommendations for the use of tiagabine as an adjunct to enzyme-inducing antiepileptic drug therapy in adult and adolescent patients with partial epilepsy differ between the US and Europe. In the US in adults, tiagabine should be initiated at a dosage of 4 mg once daily, which may be increased by 4 to 8 mg/day at weekly intervals until clinical response is achieved or a maximum dosage of 32 to 56 mg/day (administered in 2 to 4 divided doses) is reached. In adolescents (aged 12 to 18 years), the maximum recommended dosage is ≤32 mg/day.

In contrast, European guidelines recommend an initial dosage of 7.5 to 15 mg/day in adults and adolescents (aged >12 years), followed by weekly incremental increases of 5 to 15 mg/day; the usual maintenance dosage is 30 to 50 mg/day administered in 3 divided doses. If cessation of tiagabine therapy is necessary, the dosage should be reduced gradually over a period of 2 to 3 weeks.

Tiagabine should be administered with food, and dosage reduction may be necessary in patients with mild or moderate hepatic impairment. In Europe tiagabine is contraindicated in patients with severe hepatic impairment. There are currently insufficient data to recommend the use of tiagabine in pregnant or lactating women.


Adis International Limited Status Epilepticus Antiepileptic Drug Partial Seizure Seizure Frequency 
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© Adis International Limited 1998

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  1. 1.Adis International LimitedMairangi Bay, Auckland 10New Zealand

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