What is the role of tiagabine (TGB) in the treatment of epilepsy?

Updated: Jan 28, 2020
  • Author: Juan G Ochoa, MD; Chief Editor: Selim R Benbadis, MD  more...
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Tiagabine (TGB) is a derivative of the GABA uptake inhibitor nipecotic acid. It acts by inhibition of the GABA transporter-1 (GAT-1). This inhibitory effect is reversible. TGB is lipid soluble and thus is able to cross the blood-brain barrier. It was introduced into clinical practice in 1998. Measurements in human and experimental models have confirmed that extracellular GABA concentrations increase after administration of TGB. Studies have shown little or no effect at other receptor systems.

The oral bioavailability of TGB is approximately 96%. The time to peak concentrations is approximately 1 hour after oral intake. A second peak of the plasma concentration of TGB is seen 12 hours after ingestion, probably caused by enterohepatic circulation. Food decreases absorption 2- or 3-fold; however, the total amount absorbed is unchanged by food administration.

TGB’s volume of distribution is 1 L/kg, and the drug is bound extensively (ie, 96%) to human plasma proteins. It is metabolized extensively in the liver by the P-450 system. None of the TGB metabolites has any antiepileptic action, and less than 3% of the drug appears unchanged in the urine.

The plasma half-life of TGB has been found to range from 4.5 to 8.1 hours in healthy volunteers, and this is reduced to 3.8-4.9 hours in patients with epilepsy who are comedicated with enzyme-inducing drugs. The clearance of TGB is greater in children. The elimination of the drug is reduced in patients with mild to moderately severe liver impairment.

TGB causes a small decrease in valproate (VPA). It has no significant effects on plasma concentrations of progesterone, estradiol, follicle-stimulating hormone, or luteinizing hormone. Hepatic-inducing drugs increase the clearance of TGB by two thirds. TGB plasma concentrations are not affected by VPA, cimetidine, or erythromycin.

TGB has been studied as adjunctive therapy in 5 double-blind, placebo-controlled studies, which demonstrated its efficacy. Besides these 5 studies, TGB has been the subject of other clinical trials designed to demonstrate efficacy, including 3 trials (1 open and 2 double-blinded) in monotherapy and 6 open long-term studies. In a meta-analysis comparing these results with placebo-controlled, randomized trials of other drugs, no significant differences in efficacy were demonstrated among TGB, gabapentin, lamotrigine (LTG), topiramate, vigabatrin (VGB), and zonisamide (ZNS).

In the long-term extension studies, 772 patients were treated with TGB (< 80 mg/d), with reduction in seizure frequency by 50% or more in about 30-40% of patients treated for 3-6 months. This effect was maintained for 12 months in patients with partial seizures but not in patients with secondarily generalized seizures. The drug is available for use as second-line add-on therapy in patients with partial or secondarily generalized seizures that are refractory to treatment.

In the United States, the recommended dosage is 4 mg/d with a titration of 4-8 mg/d each week, and the usual maintenance dose is 32-56 mg/d. In Europe, the recommended dose is 15 mg/d followed by weekly incremental increases of 5-15 mg up to a maximum of 15-30 mg/d. In patients on concomitant enzyme inducers, the dose could be increased gradually to 45 mg/d.

The most troublesome adverse effects of TGB include dizziness, asthenia, nervousness, tremor, depressed mood, and emotional lability. Diarrhea also is significantly more frequent among TGB-treated patients than placebo-treated patients. Other adverse effects include somnolence, headaches, abnormal thinking, abdominal pain, pharyngitis, ataxia, confusion, psychosis, and skin rash. No changes in biochemical or hematologic parameters are reported. Serious idiosyncratic adverse effects are recorded as commonly in patients on placebo as in those on TGB.

A few clinical trials have reported the occurrence of convulsive and nonconvulsive status epilepticus with TGB. In the author’s experience, 1 case of nonconvulsive status was caused by accidental overdose. TGB therapy should be used cautiously in patients with a history of status epilepticus. TGB is contraindicated in severe hepatic impairment, pregnancy, and lactation.

Use of TGB is limited to adjunctive therapy in refractory partial epilepsy. It should not be used in absence epilepsy or in partial epilepsies with generalized spike wave, since it can worsen seizure control or cause status epilepticus.

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