Tiagabine

Abstract

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. 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-HT_1B or dopamine D₁ or D₂ receptors or β₁₋ or β_{2−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. 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...