Retigabine acts via a different mechanism of action to other antiepileptics, primarily by opening the neuronal potassium channels KCNQ2 (Kv7.2) and KCNQ3 (Kv7.3). This stabilises the resting membrane potential, thereby suppressing epileptiform firing.
Other mechanisms by which retigabine exerts its anticonvulsant effect have yet to be fully elucidated, but data indicate that the drug may be a GABA enhancer.1,2 At clinically relevant concentrations, retigabine does not alter the activity of the Kv7.1 potassium channel, which plays a key role in cardiac action potential repolarisation.3
As retigabine is not metabolised by cytochrome P450 enzymes, it is thought to have few interactions with other antiepileptics, although clearance of retigabine is increased by carbamazepine and phenytoin.1
Three randomised, placebo-controlled, double-blind studies evaluated the use of retigabine as adjunctive therapy in patients with uncontrolled partial-onset seizures despite treatment with up to three antiepileptic drugs. If patients experienced ≥4 seizures per 28 days, without a seizure-free period of ≥21 days during an 8-week baseline period, they were eligible to enter the studies.
In all studies, the primary efficacy measure was the percentage change in monthly seizure frequency from baseline and the secondary efficacy measure was response rate (defined as the proportion of patients with a ≥50 per cent reduction in seizure frequency from baseline).2–4
An initial dose-ranging recruited 399 patients. Following the baseline phase, patients entered a 16-week treatment period (including 8-week titration and 8-week maintenance phases) in which they received retigabine 600mg, 900mg or 1200mg daily in 3 divided doses, or placebo. The intention-to-treat analysis showed greater reductions in monthly seizure frequency and higher response rates for the 900mg and 1200mg doses compared with placebo.2
The trial enrolled 306 patients. After the baseline phase, patients started an 18-week treatment phase (including 6-week titration and 12-week maintenance phases) in which they received either retigabine 1200mg daily in three divided doses, or placebo. The intention-to-treat analysis revealed a significant reduction in monthly seizure frequency for retigabine compared with placebo (44.3% vs 17.5%; p<0.001). In addition, the response rate was significantly higher in the treatment arm than in the placebo arm (44.4% vs 17.8%; p<0.001).3
The trial assessed lower daily doses of retigabine (600mg or 900mg) in 3 divided doses versus placebo in 538 patients. Treatment comprised a 4-week titration phase and a 12-week maintenance phase. Again, seizure frequency was reduced to a greater extent in both treatment arms (600mg, 27.9%; 900mg, 39.9%) compared with the placebo arm (15.9%; p=0.007 and p<0.001, respectively) and response rates were higher for retigabine than placebo (38.6% and 47.0%, respectively vs 18.9%; p<0.001 for both).4
In open-label extensions of the trials over ?12 months (n=365), retigabine demonstrated continued efficacy.1
During these trials, the most commonly recorded adverse events were dizziness, somnolence and fatigue. Urinary tract dysfunction and psychiatric reactions occur less commonly, but it is recommended that patients are advised about the risk of these effects.1–4
Further Information: GlaxoSmithKline