Epilepsy affects more than 50 million people worldwide and has an estimated prevalence of 0.4–1%.[1,2] Partial seizures result from abnormal firing of neurons in a localised area of the brain and can be broadly classified as simple or complex.[3] Although simple partial seizures do not involve impairment of consciousness, they can be associated with motor, somatosensory, autonomic or psychic symptoms. Complex partial seizures may have similar symptomatology but also involve impairment of consciousness. Both simple and complex partial seizures may evolve to generalised seizures.[3]

A wide range of anticonvulsant drugs can be used to treat partial seizures, although carbamazepine or valproic acid (sodium valproate) are commonly used as first-line therapy.[3] Many newer anticonvulsants have also demonstrated good efficacy in the treatment of partial seizures and may be better tolerated than standard first-line agents. However, resistance to currently available drugs is estimated to occur in about 30% of patients.[2]

This article focuses on retigabine [N-(2-amino-4-(4-fluorobenzylamino)-phenyl) carbamic acid ethyl ester], a novel anticonvulsant that is currently under development as adjuvant therapy in patients with partial seizures.

1. Pharmacodynamic Profile

• The pharmacodynamic effects of retigabine have been evaluated in vitro and in various animal models. Results of these studies indicate that the drug has anticonvulsant activity in a range of models and that this action results mainly from opening neuronal voltage-gated potassium channels.

• Retigabine has anticonvulsant properties that appear to be primarily mediated by opening or activating neuronal voltage-gated potassium channels.[4–9] This action has been shown in neuronal KCNQ2/3[4,8] and KCNQ3/5[7,9] potassium channels. These voltage-gated potassium channels, which are thought to underlie the M-current,[4,7,8] are abundant in regions associated with epileptiform activity and appear to play an important role in the control of neuronal excitability.[7,8] In Chinese hamster ovary cells transfected with human KCNQ2/3 subunits, retigabine concentration-dependently activated a K+ current that was partially blocked by the KCNQ2/3 (and M-channel) antagonist linopirdine.[4,8]

• In addition to this unique mechanism of action, retigabine also potentiates GABA-evoked currents, although the contribution of this mechanism to the anticonvulsant activity of retigabine appears to be limited, as this effect has been shown only at high concentrations.[5] In rat cortical neurons, significant GABA potentiation occurred only at retigabine concentrations >10 µmol/L (>3033 ng/mL), whereas K+ channel opening was observed at concentrations as low as 0.1 µmol/L (30.3 ng/mL).

• Other effects that may contribute to the anticonvulsant (or a potential neuroprotective) action of retigabine include blockade of 4-aminopyridine-induced stimulation of glutamate release and stimulation of de novo GABA synthesis, as demonstrated in rat hippocampus in vitro and/or in vivo.[10,11]

• Retigabine has demonstrated a broad range of anticonvulsant activity in animal models of epileptic seizures.[12–14] These include electrically induced (amygdala kindling,[13] maximal electroshock[12]), chemically induced (pentylenetetrazole, picrotoxin and NMDA)[12] and sound-induced[14] seizures, the latter being in epilepsy-prone rats. In addition, retigabine demonstrated anticonvulsant properties in a genetic animal model, the DBA/2 mouse.[12]

• In the amygdala kindling model of complex partial seizures in rats, oral and intraperitoneal administration of retigabine increased the threshold for induction of afterdischarges in a dose-dependent manner, with significant effects observed with doses as low as 0.01 mg/kg.[13] In addition, retigabine was associated with reduced seizure severity and duration when administered at higher dosages (2.5–5 mg/kg intraperitoneally or 10–15 mg/kg orally). Results indicated that retigabine was more effective in the amygdala kindling model of complex partial seizures than in other seizure models.

• Retigabine also reduced behavioural and electrographic seizures in the lamotrigine-resistant amygdala kindled rat model of drug-resistant epilepsy.[15] Intraperitoneal administration of retigabine 10–40 mg/kg dose-dependently blocked the expression of the behavioural seizure and decreased the after-discharge duration in both lamotrigine-sensitive and -resistant rats.

2. Pharmacokinetic Profile

The pharmacokinetic properties of retigabine and its potential for pharmacokinetic drug interactions have been evaluated in healthy volunteers and patients with partial seizures. In general, results of these studies indicate that retigabine has a suitable pharmacokinetic profile for use as an oral anticonvulsant agent and is associated with few clinically significant drug interactions. A summary of mean pharmacokinetic values for single-dose administration of retigabine 300mg is presented in the Features and Properties table.[16]

• The absolute bioavailability of orally administered retigabine is 60%.[17] Absorption of retigabine is rapid, with peak plasma concentrations (Cmax) achieved after a mean of 0.9–2.1 hours (tmax) following single- or multiple-dose oral administration of the drug to healthy volunteers.[16] After single-dose administration of 100–300mg, mean values for tmax ranged from 1.4 to 1.8 hours and those for Cmax increased linearly from 414 ng/mL to 1071 ng/mL. Similar results were reported after 14 days’ administration of retigabine 100–350mg every 12 hours: Cmax values of 498–1593 ng/mL were achieved after 0.9–2.1 hours.[16]

• Mean values for area under the plasma concentration-time curve (AUC) increased linearly in a similar fashion to Cmax values. After single-dose administration of retigabine 100, 200 and 300mg in healthy volunteers, AUC values were 1831, 5134 and 7823 ng · h/mL, respectively.[16] The volume of distribution calculated after oral administration (Vd/F) ranged from 6.2 to 8.8 L/kg after single-dose and from 5.1 to 7.4 L/kg after multiple-dose administration of retigabine.[16]

• Elimination half-life (t1/2) ranged from 7.4 to 9.2 hours following single-dose administration of retigabine and from 6.8 to 7.2 hours at steady state (all mean values).[16] Corresponding ranges of mean values for apparent oral clearance were 0.53–0.72 and 0.51–0.71 L/h/kg.

• Intrasubject variability of retigabine pharmacokinetics was generally <30%.[16] There was some diurnal variation in the pharmacokinetics of retigabine at steady state; trough plasma retigabine concentrations were approximately 35% lower in the evening than in the morning. In addition, retigabine exposure was greater in Black than in White individuals as a result of 25–30% lower apparent oral clearance and volume of distribution in Black volunteers.[16]

• In addition, a pharmacokinetic drug interaction study confirmed and extended previous data, indicating that retigabine pharmacokinetics are linearly dose-proportional up to a dosage of 1200 mg/day in patients with epilepsy.[18]

• The metabolic fate of retigabine has been determined primarily in rats and dogs, although analysis of metabolites isolated from urine samples of healthy human volunteers indicate that both acetylation and glucuronidation are metabolic pathways.[19] The major metabolite of retigabine is an N-glucuronide substituted at the primary amino group. Additional metabolites include another N-glucuronide substituted at the secondary amino group, as well as an N-acetyl metabolite.[19] The major retigabine N-glucuronosyl transferase in vivo has been identified as UGT1A4 and it contributes to enterohepatic cycling of the drug.[20] The main route of elimination of the metabolites and parent drug is via the urine (84% of a 14C-labelled dose is recovered in the urine as parent drug or metabolites).[17]

• The pharmacokinetics of the partially active N-acetyl metabolite were evaluated in healthy male volunteers.[16] Results showed that, like the parent compound, the pharmacokinetics of the acetylated metabolite were approximately dose linear. Cmax of the acetylated metabolite occurs approximately 1.5 hours after that of the parent compound and its t1/2 (6.2–8.6 hours) is similar to that of retigabine. Plasma concentrations of the acetylated metabolite were broadly similar to those of the parent drug.[16]

• A number of studies have investigated potential pharmacokinetic drug interactions between retigabine and other concurrently administered drugs in healthy volunteers[21–24] and patients with epilepsy.[18] Results of these studies showed no clinically relevant interactions when retigabine was co-administered with phenobarbital,[21] valproic acid[18] or topiramate.[18] As with other anticonvulsant drugs, the clearance of retigabine was increased by phenytoin and carbamazepine; retigabine did not affect the pharmacokinetics of these drugs.[18]

• A study evaluating the concomitant administration of retigabine and lamotrigine generally showed no clinically significant pharmacokinetic interaction, although modest and statistically significant changes in some parameters were noted.[24] These included increased AUC and t1/2 values for retigabine (with concurrent administration of low-dose lamotrigine) and reduced AUC and t1/2 values for lamotrigine.

• Concurrent administration of retigabine (150mg three times daily on days 10–13) in women taking oral contraceptives did not affect the pharmacokinetics of ethinylestradiol and norgestrel.[23]

3. Therapeutic Efficacy

The clinical efficacy of retigabine as adjunctive therapy in patients with partial seizures has been demonstrated in a large phase II trial and an open-label extension of the study. These studies showed significant anticonvulsant activity when the drug was administered for up to approximately 1 year.

The clinical efficacy of retigabine in patients with partial seizures has been evaluated in a large, double-blind, placebo-controlled, randomised, multinational phase II trial[25,26] and an open-label extension of the study.[27] As these trials have not yet been published, data presented in this section are from abstract reports,[26,27] supplemented with data from the company developing the drug.[25]

Following an 8-week baseline period, patients were randomised to receive adjunctive therapy with one of three retigabine regimens (600, 900 or 1200 mg/day in three divided doses) or matching placebo for 16 weeks.[25,26] This included an 8-week forced-titration period and an 8-week maintenance period. During the titration period, patients in the active treatment arms received retigabine 100mg three times daily during the first week, which was then increased by 150 mg/day (50mg three times daily) at weekly intervals until the target dosage was achieved. Dosage reductions were permitted during the last 2 weeks of the titration phase but not during the maintenance period.

The study included patients (aged 16–70 years) who experienced ≥4 partial seizures per month during the 8-week baseline period with no 30-day seizure-free period.[25,26] This was despite receiving stable doses of one or two anticonvulsant agents during the baseline phase. The primary endpoint was the change in monthly frequency of partial seizures during the 16-week study period compared with the 8-week baseline phase. Data were collected using patient diaries that were presented to investigators during clinic visits. An important secondary endpoint was responder rate, defined as the proportion of patients with ≥50% reduction in seizure frequency.

• In the intent-to-treat (ITT) efficacy analysis (n = 396), median monthly seizure frequency decreased from baseline by 23% among patients in the 600 mg/day arm, 29% in the 900 mg/day arm, 35% in the 1200 mg/day arm and 13% in the placebo group (figure 1).[25,26] The difference was statistically significant for comparisons between retigabine 900 mg/day and placebo (p = 0.043) and between retigabine 1200 mg/day and placebo (p < 0.001). Across the three dosage levels, retigabine was associated with a linear dose-dependent reduction in seizure frequency that was significantly greater than the reduction achieved with placebo (p < 0.001). The difference between retigabine 1200 mg/day and 600 mg/day was also statistically significant (35% vs 23%; p = 0.047).

Fig. 1
figure 1

Seizure frequency reduction with retigabine as adjuvant therapy in a large phase II trial in patients with partial seizures.[25,26] Change from baseline in monthly frequency of partial seizures during the 16-week double-blind treatment period (intent-to-treat analysis). * p = 0.043, ** p < 0.001 vs placebo; † p = 0.047 vs retigabine 600 mg/day.

Full size image

• In patients who completed the double-blind treatment period (n = 279) results were similar, with reductions in seizure frequency of 27%, 34%, 39% and 14% in the 600 mg/day, 900 mg/day, 1200 mg/day and placebo groups, respectively.[25]

• Responder rates in the ITT analysis were significantly higher among patients in the retigabine 900 mg/day (32%) and 1200 mg/day (33%) groups than in those who received placebo (16%) [both p < 0.05].[25,26] The responder rate was 23% in the retigabine 600 mg/day arm, which was not statistically different from that in the placebo group.

• A total of 222 patients who completed the double-blind phase II trial participated in an open-label extension study in which all patients’ regimens were converted to retigabine 900 mg/day (300mg three times daily).[27] Dosages of anticonvulsant drugs, including retigabine, could then be modified at the discretion of the investigator. During the first 6 months of the extension period, the median reduction from baseline in monthly seizure frequency was 48% and the responder rate was 46%. The most common dosage of retigabine was 900 mg/day (47%) and less than one-quarter of patients (23%) received the maximum dosage of 1200 mg/day.

4. Tolerability

Retigabine was generally well tolerated in clinical trials conducted to date. Most adverse events associated with retigabine were CNS-related effects.

Tolerability data for retigabine in patients with partial seizures are derived from the large phase II trial[25,26] and its extension study[27] described in section 3, as well as a smaller randomised, double-blind phase II trial designed to evaluate the tolerability of different dosage titration schedules of retigabine as adjunctive therapy (data provided by the manufacturer)[28] and an open-label dose-finding study of similar size (reported as an abstract).[29]

The randomised, double-blind, multinational, dosage-titration tolerability study included 73 patients (aged 16–70 years) who had experienced ≥2 partial seizures during the 4 weeks prior to screening, despite being maintained on stable doses of one or two anticonvulsant agents.[28] Patients remained on stable doses of anticonvulsant therapy and were randomised to receive adjunctive treatment with retigabine for 49 days according to one of three titration schedules. All patients received retigabine 300 mg/day (100mg three times daily) on day 1, then the dosage was increased by 150 mg/day (50mg three times daily) every 2, 4 or 7 days in the fast-, medium- and slow-titration groups, respectively. Patients who were unable to reach the target dosage of 1200 mg/day because of adverse events were withdrawn from the study. This was also the primary outcome of the trial, which was evaluated in a modified ITT population (n = 68) that excluded patients who withdrew from the study for reasons other than adverse events.[28]

• The main findings of the dosage-titration tolerability study are presented in figure 2. The primary outcome analysis in the modified ITT population showed that significantly more patients in the fast- than in the slow-titration group discontinued retigabine because of adverse events (43.5% vs 13.0%; p = 0.024).[28] The difference between medium- and slow-titration groups was not statistically significant (31.8% vs 13.0%). In general, a similar pattern was noted when results were stratified by background anticonvulsant therapy (e.g. enzyme inducers vs non-enzyme inducers) and when results were evaluated for the ITT population.

Fig. 2
figure 2

Main findings of a randomised, double-blind, 49-day dosage-titration tolerability study with retigabine.[28] Patients with partial seizures received retigabine 300 mg/day (100mg three times daily) on day 1, then the dosage was increased by 150 mg/day (50mg three times daily) every 2 days in the fast-titration group, every 4 days in the medium-titration group and every 7 days in the slow-titration group. * p = 0.024 vs slow-titration group.

Full size image

• The most frequently reported treatment-emergent adverse events in the dosage-titration tolerability study were CNS-related problems.[28] Across all three groups, the most common adverse events leading to discontinuation of retigabine were somnolence (9.6%), unspecified speech disorder (6.8%), ataxia (5.5%), dizziness (5.5%) and asthenia (5.5%).

• Most adverse events reported in the large phase II trial (n = 397) occurred during the 8-week forced-titration phase of the study, and patients in the highest retigabine dosage group (1200 mg/day) reported the highest level of adverse events.[25] The proportions of patients who withdrew from the study because of adverse events were 17%, 20% and 29% in the retigabine 600, 900 and 1200 mg/day groups, respectively, compared with 12.5% among placebo recipients. The most common adverse events leading to discontinuation of retigabine were confusion, unspecified speech disorder, dizziness and somnolence.[25]

• Across all three retigabine treatment arms (n = 301) in the large phase II trial the most commonly reported treatment-emergent adverse events were CNS-related and included somnolence (20.3%), dizziness (14.6%), confusion (12.3%) and unspecified speech disorder (11.3%) [all p < 0.05 vs placebo; see figure 3].[25]

Fig. 3
figure 3

Treatment-emergent CNS-related adverse events occurring in ≥10% of patients in the large, multicentre, phase II, forced-titration trial.[25] Patients with partial seizures (n = 397) were randomised to receive placebo or retigabine titrated to a target dosage of 600, 900 or 1200 mg/day (in three divided daily doses) in this 16-week adjuvant treatment study. * p < 0.05 for placebo vs combined retigabine groups.

Full size image

• Other, non—CNS-related treatment-emergent adverse events included headache and asthenia, both of which occurred in approximately 15% of retigabine recipients.[25] There were no noteworthy laboratory abnormalities or effects on vital signs, ECGs or neurological examinations. Serious adverse events attributed to treatment included single cases of suicidal ideation, abnormal thinking, psychosis, nausea and vertigo.[25]

• The tolerability of retigabine as adjunctive therapy was also evaluated in 60 patients with partial or generalised seizures in an open-label study of 92 days’ mean duration.[29] Dosages up to 1600 mg/day were allowed, as the study was designed to determine the maximum tolerated dosage. In general, the tolerability profile of retigabine was similar among patients who received the drug in a twice-daily regimen to those who received retigabine three times daily. In both groups the maximum tolerated dosage was 1200 mg/day. As was observed in other studies with retigabine, the most frequently reported adverse events were CNS-related, such as dizziness, asthenia and somnolence.

5. Dosage and Administration

In most phase II studies, retigabine was administered orally at a dosage of 600–1200 mg/day in three evenly divided doses (200–400mg three times daily). The initial dosage in these trials was 300 mg/day (100mg three times daily), which was gradually increased by 150 mg/day (50mg three times daily) to the target dosage. Doses were administered in the morning, at mid-day and in the evening.

6. Retigabine: Current Status

The clinical efficacy of retigabine as adjunctive therapy in patients with partial seizures has been demonstrated in a large phase II trial and an open-label extension of the study. Data from phase II trials indicate that the drug is generally well tolerated, with CNS-related adverse events reported most frequently. Retigabine is currently being evaluated in two multinational phase III studies in patients with partial seizures. In addition, future studies with retigabine may evaluate its use in other diseases such as neuropathic pain, bipolar disorder and migraine headache.

Disclosure

During the peer review process, the company developing the agent under review was also offered an opportunity to comment on this article; changes based on any comments received were made on the basis of scientific and editorial merit.