Pharmacology

The results of preclinical investigations suggest that vigabatrin and tiagabine are pharmacologically distinct compounds with different anticonvulsant, neurotoxicity, and pharmacokinetic profiles. It is possible that they will ultimately prove to have different clinical efficacies and spectra of activity. The molecular formula of tiagabine is C20 H25 NO2 S2 HCl.

Pharmacodynamics. The precise mechanism of the antiseizure effect of tiagabine is unknown, although it is believed to be related to its ability to enhance the activity of GABA, the major inhibitory neurotransmitter in the CNS. Tiagabine binds to recognition sites associated with the GABA uptake carrier and blocks GABA uptake into presynaptic neurons, permitting more GABA to be available for receptor binding on the surfaces of postsynaptic cells. Inhibition of GABA uptake has been shown for synaptosomes, neuronal cell cultures, and glial cell cultures. Tiagabine increases the amount of GABA available in the extracellular space of the globus pallidus and substantia nigra.

Neuroimaging study using 18F fluorodeoxyglucose-PET has shown that following tiagabine treatment, regional cerebral metabolic rate of glucose uptake in ventral medial prefrontal cortex increased significantly in patients with generalized social anxiety disorder. These findings suggest that therapeutic effects of tiagabine in this disorder may be mediated via GABAergic modulation of ventral medial prefrontal cortex. Following administration of tiagabine in healthy male volunteers, acute increases in endogenous synaptic GABA were detectable in the living human brain using [¹¹C]Ro15-4513, an inverse agonist GABA-benzodiazepine receptor PET tracer (12). Reductions in synaptic [¹¹C]Ro15-4513 binding were significant in the hippocampus, parahippocampal region, amygdala, and anterior cingulate cortex.

Experimental studies have shown neuroprotective effect of tiagabine pretreatment on the nigrostriatal axis by attenuation of microglial activation in a neurotoxin-induced mouse model of Parkinson disease (09). This finding indicates a potential application of tiagabine for treatment of Parkinson disease. Theoretically, GABA transporter blockade by drugs such as tiagabine offers an indirect approach to increase GABA inhibition to lower the excitation threshold of neurons following cerebral ischemia for neuroprotective effect. A study of several drugs on a mouse model of cerebral ischemia showed that low dose tiagabine improved motor recovery, but higher doses induced seizures, and none of the drugs reduced infarct volume (08). These findings indicate that tiagabine should be used with caution in cases of cerebral ischemia.

Pharmacokinetics. Features of pharmacokinetics of tiagabine are:

The pharmacokinetics of total and unbound tiagabine are unaffected in subjects with renal failure requiring hemodialysis.

Clinical trials

Several open studies of tiagabine were conducted to evaluate it as an add-on therapy in partial seizures. Several controlled clinical trials were also conducted with tiagabine as an add-on therapy.

The Cochrane Database Systematic Review of Controlled Clinical Trials concluded that tiagabine reduced seizure frequency, but was associated with some adverse effects when used as an add-on treatment in patients with drug-resistant focal epilepsy (02).

According to a review of use of tiagabine in clinical practice, behavioral adverse events occurred in a larger proportion of patients compared to those reported in tiagabine preapproval randomized controlled trials, but a moderate percentage of patients did have a meaningful reduction in seizure frequency (16). It was concluded that tiagabine is a useful antiepileptic drug in clinical practice.

Indications

Tiagabine hydrochloride is indicated as adjunctive therapy in the treatment of partial seizures in adults and children 12 years and older.

Off-label uses

Contraindications

Tiagabine is contraindicated in patients who have demonstrated hypersensitivity to the drug or its ingredients.

Goals and duration of treatment

The aim is control of partial seizures by reduction in frequency. Dosage adjustment may be necessary, and the drug can be used for an indefinite period. Results of an open, prospective study of effectiveness of tiagabine in Bulgarian patients with drug-resistant epilepsy showed low and transient improvement of seizure severity, good and stable improvement of seizure frequency, possible appearance of new seizure types, and acceptable safety (15).

Dosing

In adolescents and adults, tiagabine should be initiated at 4 mg once daily. The total daily dose may be increased by 4 mg at the beginning of week 2. Thereafter, the total daily dose may be increased by 4 to 8 mg at weekly intervals until clinical response is achieved, or up to 32 mg per day. The total daily dose should be given in divided doses 2 to 4 times daily. Modification of concomitant antiepileptic drugs is not necessary.

Special considerations

In patients with moderate hepatic impairment, clearance of unbound tiagabine is reduced by about 60%. These patients may require reduced initial and maintenance doses of tiagabine or longer dosing intervals compared patients with normal hepatic function.

Pediatric. Tiagabine has not been investigated in adequate and well-controlled clinical trials in patients below the age of 12 years.

Geriatric. The pharmacokinetic profile of tiagabine is similar in healthy elderly and healthy young adults.

Pregnancy. Because teratogenic effects were seen in the offspring of rats exposed to maternally toxic doses of tiagabine, and because experience in humans is limited, patients should be advised to notify their physicians if they become pregnant or intend to become pregnant during therapy. Because of the possibility that tiagabine may be excreted in breast milk, and because there is limited published experience with tiagabine during breastfeeding, other antiepileptic agents may be preferred.

Anesthesia. No adverse interaction with anesthetic agents have been reported

Interactions

The clearance of tiagabine is affected by the coadministration of hepatic enzyme-inducing antiepileptic drugs leading to more rapid clearance and loss of efficacy. Acute tiagabine toxicity due to raised serum levels due to pharmacokinetic drug interaction with concomitantly administered gemfibrozil has been reported (03).

Adverse effects

Adverse events most often associated with the use of tiagabine are related to the central nervous system. The most significant of these can be classified into 2 general categories: (1) impaired concentration, speech or language problems, and confusion (effects on thought processes); and (2) somnolence and fatigue (effects on level of consciousness). Patients with a history of spike and wave discharges on EEG have been reported to have exacerbations of their EEG abnormalities associated with these cognitive and neuropsychiatric events. Tiagabine-related stupor has been reported in a few cases and may represent a form of toxic encephalopathy (01). Tiagabine-induced myoclonic status epilepticus has been reported in a nonepileptic patient. Nonconvulsive status epilepticus may occur after a slight increase in tiagabine dose, but outcome is favorable with tiagabine withdrawal and use of benzodiazepine. Generalized convulsive status epilepticus is a complication of voluntary or involuntary tiagabine poisoning and can be refractory. Recovery is the rule after tiagabine withdrawal and management of status epilepticus with progressive therapeutic escalation guided by response to prior anticonvulsant treatments (07). For details of adverse events, see the Physicians’ Desk Reference.

In 2005 and 2008, the FDA issued warnings on the risk of seizures in nonepileptic and increased suicide ideation with use of tiagabine. A retrospective review of all single substance tiagabine exposures in the National Poison Data System showed a significant decline of reported cases between 2005 and 2006 and no deaths, reflecting the drop in sales of the drug following warnings (11). Clinical manifestations of reported cases were mainly neurologic, with suicide attempts as the most frequent, and the majority were treated at a healthcare facility.

Management. Most of the neurologic adverse reactions can be resolved by reduction of dose or discontinuation of tiagabine.