Clinical Significance of Animal Seizure Models and Mechanism of Action Studies of Potential Antiepileptic Drugs

Summary: More than 50 million persons worldwide suffer from epilepsy, many of whom are refractory to treatment with standard antiepileptic drugs (AEDs). Fortunately, new AEDs commercialized since 1990 are improving the clinical outlook for many patients. Our growing understanding of anticonvulsant mechanisms and the relevance of preclinical animal studies to clinical antiepileptic activity have already contributed to the design of several new AEDs and should be increasingly beneficial to further efforts at drug development. Mechanisms have been identified for older AEDs [phenytoin (PHT), carbamazepine (CBZ), valproate (VPA), barbiturates, benzodiazepines (BZDs), ethosuximide (ESM)] and newer AEDs [vigabatrin (VGB), lamotrigine (LTG), gabapentin (GBP) tiagabine (TGB), felbamate (FBM), topiramate (TPM)]. Several novel anticonvulsant mechanisms have recently been discovered. FBM appears to be active at the strychnine-insensitive glycine binding site of the NMDA receptor. TPM is active on the kainate/AMPA subtype of glu-tamate receptor and at a potentially novel site on the GABA_A receptor. For several reasons, availability of a single AED with multiple mechanisms of action may be preferred over availability of multiple AEDs with single mechanisms of action. These reasons include ease of titration, lack of drug-drug interactions, and reduced potential for pharmacodynamic tolerance.     

Tiagabine, a novel antiepileptic agent: lack of pharmacokinetic interaction with digoxin

Objective: To assess the possibility of any clinically relevant pharmacokinetic interactions between tiagabine, a novel antiepileptic drug, and digoxin. Methods: Potential pharmacokinetic interactions between tiagabine and digoxin were investigated in an open-label, two-period cross-over study in healthy male volunteers. Thirteen volunteers, aged between 18 and 43 years, were randomised to receive digoxin (0.5 mg twice a day for 1 day, then 0.25 mg once a day for 8 days) either alone or co-administered with tiagabine (4 mg three times daily for 9 days). Following a 7-day wash-out period, volunteers crossed over to the other dosing regimen. Peak serum concentration, time to maximum serum concentration, area under the serum concentration–time curve from zero to 24 h and steady state serum concentration were calculated for digoxin and compared between treatment groups. Results: No statistically significant differences between treatment groups were observed for any of the derived digoxin pharmacokinetic parameters. The most common adverse events reported during digoxin alone and in combination with tiagabine were somnolence and headache; an overall greater frequency of adverse events was reported during combined treatment. Adverse events were generally mild in nature; no serious adverse events were reported. Conclusions: At the doses administered, there is no evidence of a pharmacokinetic interaction between digoxin and tiagabine in healthy male volunteers. Received: 21 July 1997 / Accepted in revised form: 14 January 1998     

Tiagabine and vigabatrin reduce the severity of NMDA-induced excitotoxicity in chick retina

The possible neuroprotective effects of two GABAergic drugs, tiagabine (TGB) and vigabatrin (VGB), against N-methyl-d-aspartate (NMDA)-induced excitotoxicity have been investigated in the isolated chick embryo retina model. Retina segments were incubated either with NMDA alone (100 μM) or with NMDA and TGB or VGB (10–1,000 μM, added 5 min before NMDA). Retina damage was assessed after 24 h by measuring lactate dehydrogenase (LDH) activity present in the medium and by histological analysis. Both drugs reduced LDH release in a dose-dependent manner with comparable mean maximal values of 56.6–63.7% achieved at concentration of 1 mM. Histological analysis of retina slices was in line with the biochemical assays and showed partial preservation of drug exposed retina structure with reduced edema especially in the inner plexiform layer. The present data provide pharmacological evidence that both TGB and VGB reduce the severity of NMDA-induced excitotoxic damage. Although an increase in GABAergic transmission might play a role, this in itself is insufficient to explain the neuroprotective effect of the two drugs and the exact mechanism remains to be elucidated.     

The γ-aminobutyric acid (GABA) uptake inhibitor, tiagabine, increases extracellular brain levels of GABA in awake rats

The effect of systemic administration of the γ-aminobutyric acid (GABA) uptake inhibitor, R( − )N-(4,4-di(3-methyl-thien-2-yl)-but-3-enyl) nipecotic acid, hydrochloridc (tiagabine) (previously NO-328), on extracellular GABA levels in the globus pallidus, ventral pallidum and substantia nigra of awake Sprague-Dawley rats was investigated using in vivo microdialysis. Tiagabine was administered in doses of 11.5 or 21.0 mg/kg i.p. (ED₅₀, and ED₈₅ doses, respectively, for inhibiting pentylcnctetrazole-induced tonic seizures). Tiagabine increased the extracellular concentrations of GABA in globus pallidus with peak values 310% of basal level (after 21 mg/kg) and 240% of basal level (after 11.5 mg/kg). A significant increase in extracellular GABA levels was also found in the ventral pallidum (280% increase after 11.5 mg/kg and 350% increase after 21 mg/kg) and in the substantia nigra where the ED₈₅ dose of tiagabine 621 mg/kg) produced a peak value of 200% compared to the basal level. Thus, tiagabine acts as a GABA uptake inhibitor in vivo also.     

Tiagabine in Clinical Practice

Summary: Among the newly introduced antiepileptic drugs (AEDs), tiagabine (TGB) stands out as a compound with a well-understood and documented mechanism of action. It is a lipophilic derivative of nipecotic acid that blocks γ-aminobutyric acid (GABA) reuptake by inhibition of the GAT-1 transportation system, and that has no other significant pharmacodynamic effect. The relationship between intake and blood levels is linear. Usual daily maintenance doses range from 20 to 50 mg. It is completely absorbed by the gastrointestinal tract, and its half-life is ∼7–9 h. TGB is sensitive to enzyme induction: when coprescribed with enzyme-inducing AEDs, its half-life is shortened to 2–3 h, whereas the daily dosage has to be increased into the upper range. It should be given 3 times per day. Placebo-controlled, double-blind, add-on studies conducted in patients with drug-resistant focal epilepsies have demonstrated its efficacy and overall safety. The clinical benefits appear to persist over time. Data on its use in monotherapy are scanty. The efficacy and tolerability of TGB in the pediatric age still remain to be investigated adequately. In daily practice, TGB appears to be a safe drug, but mild to moderate side effects are frequently seen, especially during titration: these include dizziness and fatigue, and are clearly abated when the drug is absorbed during meals. Titration should be especially slow, no faster than 5 mg weekly. Clinicians also should beware of the possible occurrence of confusion, which may be misdiagnosed as absence status, a short-lasting, quickly reversible central nervous system–related side effect that appears to be correlated with the peak plasma concentrations of TGB. Particularly beneficial indications for TGB and/or AED associations including TGB have not been pointed out, but there is a hint that it works best in temporal lobe epilepsies.     

Pharmacokinetics and Safety of Tiagabine in Subjects with Various Degrees of Hepatic Function

Summary: Purpose: To evaluate the pharmacokinetics and safety of multiple oral doses of tiagabine HC1 in subjects with different degrees of hepatic impairment. Methods: Four subjects with mild hepatic impairment, three subjects with moderate hepatic impairment, and six matched normal subjects received twice daily oral tiagabine HCl for 5.5 days. Serial blood specimens were obtained for 48 h after the final dose. Total and unbound tiagabine plasma concentrations were determined by high-performance liquid chromatography (HPLC) and ultrafiltration, respectively. Pharmacokinetic parameters were compared between the groups by analysis of covariance. Results: For total tiagabine concentrations in normal subjects and subjects with mild and moderate hepatic impairment, C_max values (mean i SD) were 117 ± 54, 172 ± 40, and 172 ± 28 ng/ml; C_min values were 13 ± 4,27 ± 4, and 28 ± 6 ng/ml; areas under the plasma concentration-time curve were 396 ± 59, 633 ± 16, and 675 ± 32 ng Wml, and elimination half-lives (harmonic means) were 7, 12, and 16 h, respectively. Unbound tiagabine coricentrations, area under the unbound plasma concentration-time curve, and the free fractions were increased in the hepatically impaired subjects. Reduced serum albumin and α₁-acid glycoprotein concentrations may have contributed to increases in the unbound fraction. Adverse events observed included dizziness, tremor, nausea, somnolence, incoordination, and unsteady gait. The frequency of these events was increased in the subjects with liver impairment. Conclusions: Because of the decreased drug elimination caused by liver function impairment, reduced doses or increased dosing interval or both may be needed to attain therapeutic plasma drug concentrations. Time to reach steady state also may be prolonged. The patients should be monitored closely for potential neurologic adverse events.     

Elderly Patients with Epilepsy: Specific Requirements

Summary: Epilepsy is the third most common neurologic disorder in the elderly and, combined with the progressive aging of the population, this high incidence will lead to an increasing number of elderly patients who require epilepsy care. Treatment of epilepsy in elderly patients is often complicated by the physiologic changes that occur in old age, e.g., reduced absorption, slower metabolism, and deterioration of liver and renal function. Another consideration is that elderly patients are most likely to be suffering from other diseases, necessitating multiple therapies. The potential for drug interactions is therefore high. Because of these factors, traditional antiepileptic drug (AED) therapies are associated with a higher incidence of adverse effects in elderly patients than in younger patients. Tiagabine (TGB) is one of a family of new AEDs recently developed. The newer AEDs tend to have a comparable antiepileptic efficacy and a lower potential for toxicity compared with the traditional AEDs. Clinical studies have shown that age appears to have no effect on the pharmacokinetics of TGB and that there is little difference in the incidence of adverse events between elderly and young patients. Although clinical experience with TGB in the elderly is still limited, TGB shows promise for treatment of epilepsy in the elderly population.     

Effects of tiagabine in combination with intravenous nicotine in overnight abstinent smokers

Rationale Preclinical studies suggest that medications enhancing the brain gamma amino butyric acid (GABA) system attenuate the rewarding effects of stimulants including nicotine. These preclinical studies have not been followed up in systematic human studies. Objectives This study was conducted to examine the effects of a GABAergic medication, tiagabine, on acute physiological and subjective effects of intravenous (i.v.) nicotine and on tobacco withdrawal symptoms in overnight abstinent smokers. The proposed mechanism of action for tiagabine is selective inhibition of GABA transporter type I, which leads to increases in synaptic GABA levels. Methods Eight male and four female smokers participated in a double-blind, placebo-controlled, crossover study. In each of three experimental sessions, participants were treated orally with a single 4- or 8-mg dose of tiagabine or placebo. Two hours following the medication treatment, participants received i.v. saline, followed 30 min later by 1.5 mg/70 kg i.v. nicotine. Results Tiagabine treatment did not affect the heart rate or blood pressure changes induced by nicotine. There was a significant treatment effect for the subjective responses to nicotine, such that tiagabine, compared to placebo, attenuated the ratings of “good effects” and “drug liking.” Tiagabine treatment at 8 mg attenuated the craving for cigarettes and enhanced the cognitive performance in the Classical Stoop Tests, compared to placebo or 4 mg tiagabine condition. Conclusions These results suggest that GABA enhancing medication tiagabine may reduce the rewarding effects of nicotine and improve cognitive performance in abstinent smokers. The utility of GABA medications for smoking cessation needs to be examined further in controlled clinical trials.     

Status Epilepticus and Tiagabine Therapy: Review of Safety Data and Epidemiologic Comparisons

PURPOSE: To determine whether an increased risk of status epilepticus (SE) and complex partial status epilepticus (CPSE) is associated with tiagabine (TGB) therapy. METHODS: Thirteen cases in which an EEG, performed on patients with altered mental status taking TGB, was reported to demonstrate spike-and-wave discharges (SWDs) were reviewed by a panel of experts. In addition, all cases of suspected SE from TGB clinical trials were reviewed. The occurrence of SE in four epidemiologic cohorts from Rochester, Minnesota, Turku, Finland, Bronx, New York, and New Haven, Connecticut was analyzed as an external comparison. RESULTS: Review of the 13 cases with reported SWDs found that the majority had had prior EEGs with similar findings, and only three were thought to have electrographic evidence of SE. There was no difference in the frequency of SE or CPSE in the placebo-controlled clinical trials between the TGB-treated (1.0% SE, 0.8% CPSE) and placebo-treated (1.5% SE, 1.5% CPSE) groups. The 5% frequency of SE and 3% frequency of CPSE in the TGB-treated patients in the long-term safety studies, which included 2,248 patients, were very similar to the rates of occurrence of SE and CPSE in the four external cohorts. The major risk factor for the occurrence of SE and CPSE in all groups was a prior episode of SE (p < 0.0001). CONCLUSIONS: Over a 3-year period, SE will occur in 5-10% of patients with epilepsy not in remission. At highest risk are those who have had a prior episode of SE. Treatment with TGB in recommended doses does not increase the risk of SE in patients with partial seizures.     

The Short-Term Impact of Adjunctive Tiagabine on Health-Related Quality of Life

Summary: Combinations of tiagabine (TGB), carbamazepine (CBZ), and phenytoin (PHT) were compared for their impact on health-related quality of life (HRQOL) and adverse effects related to treatment efficacy for people with frequent complex partial seizures. Two independent, randomized, double-blind clinical trials for efficacy and safety were conducted simultaneously with treatment groups: CBZ+PHT versus CBZ+TGB, and PHT+CBZ versus PHT+TGB. Treatment was initiated at week 0 and continued through week 16. HRQOL was evaluated with the QOLIE-89. Treatment success was defined as ≥50% reduction in complex partial seizures. Among patients who achieved a ≥50% reduction in seizures, addition of TGB to baseline PHT enhanced patient perceptions of attention/concentration (13%; p = 0.002), memory (17%; p = 0.042), and language subscales (22%; p = 0.004). Addition of CBZ to PHT led to positive change in the work/driving/social relations subscale (14%; p = 0.004). These improvements were significantly different only between visits, not between the two treatment groups. Seizure worry subscale scores showed improvement among all treatment groups and was probably related to participation in the clinical trial. These exploratory analyses suggest a possible early positive effect of TGB on patient-perceived cognitive domains using the QOLIE-89. These findings are limited by the small sample size and could be related to reduction in seizures.