Tiagabine

Tiagabine is an anti-epileptic drug.

Tiagabine is a potent and selective inhibitor of both neuronal and glial GABA uptake, which results in an increase in GABAergic medicated inhibition in the brain.

Tiagabine lacks significant affinity for other neurotransmitter receptor binding sites and/or uptake sites.

Tiagabine is rapidly and virtually completely absorbed from tiagabine tablets, with an absolute bioavailability of 89%. Administration with food results in a decreased rate and not extent of absorption.

The volume of distribution is approximately 1 L/kg.

Plasma protein binding of tiagabine is about 96%.

Renal clearance is negligible. Hepatic metabolism is the principle route for elimination of tiagabine. Less than 2% of the dose is excreted unchanged in urine and faeces. No active metabolites have been identified. Other anti-epileptic drugs such as phenytoin, carbamazepine, phenobarbital and primidone induce hepatic drug metabolism and the hepatic clearance of tiagabine is increased when given concomitantly with these drugs.

There is no evidence that tiagabine causes clinically significant induction or inhibition of hepatic drug metabolising enzymes at clinical doses.

The plasma elimination half-life of tiagabine is 7-9 hours, except in induced patients where it is 2-3 hours.

Absorption and elimination of tiagabine are linear within the therapeutic dose range.

Hepatic insufficiency

A study in patients with mild and moderate impaired liver function has shown a 50% increase of the plasma concentration peak (C_max) and a 70% increase of the area under the curve (AUC) for total (free plus bound) tiagabine in impaired individuals as compared to individuals with normal hepatic function. The fraction of unbound drug was greater in patients with moderate hepatic impairment and, as a result, exposure to unbound drug was increased to a greater extent (up to 2-fold) in moderately impaired individuals as compared to individuals with normal hepatic function. Tiagabine half-life (T_½) is prolonged in patients with impaired liver function with the extent of prolongation increasing with increased level of hepatic impairment. Due to adverse events observed in the patients with moderate impairment, patients with severe hepatic impairment were not studied.

The dosage of tiagabine should be carefully titrated in patients with epilepsy and reduced hepatic function. Lower doses or longer dosing intervals may be required in patients with mild to moderate impairment in liver function.

Animal safety data carried out in the rat, mouse and dog gave no clear evidence of specific organ toxicity nor any findings of concern for the therapeutic use of tiagabine. The dog appears to be particularly sensitive to the pharmacological actions of tiagabine and clinical signs such as sedation, insensibility, ataxia and visual impairment reflecting CNS effects were seen at daily doses of 0.5 mg/kg and above in a dose related manner. The results of a wide range of mutagenicity tests showed that tiagabine is unlikely to be genotoxic to humans.

Clastogenic activity was seen only at cytotoxic concentrations (>200-fold human plasma levels) using the in-vitro human lymphocyte test in the absence of a metabolising system. In long-term carcinogenicity studies conducted in the rat and mouse, only the rat study revealed slightly increased incidences of hepatocellular adenomas in females and benign Leydig cell tumours in the high dose (200 mg/kg/day) group only. These changes are considered to be rat-specific and macrophages and inflammation were seen at a higher incidence than normal. The significance of this latter finding is unknown.