Retigabine Other names: Ezogabine

Potassium channels are one of the voltage-gated ion channels found in neuronal cells and are important determinants of neuronal activity. In vitro studies indicate that retigabine acts primarily through opening neuronal potassium channels (KCNQ2 [Kv7.2] and KCNQ3 [Kv7.3]). This stabilises the resting membrane potential and controls the sub-threshold electrical excitability in neurons, thus preventing the initiation of epileptiform action potential bursts. Mutations in the KCNQ channels underlie several human inheritable disorders, including epilepsy (KCNQ2 and 3). The mechanism of action of retigabine on potassium channels has been well documented, however other mechanisms by which retigabine may assert an antiepileptic effect have yet to be fully elucidated.

In a range of seizure models, retigabine increased the threshold for seizure induction produced by maximal electroshock, pentylenetetrazol, picrotoxin and N-methyl-D-aspartate (NMDA). Retigabine also displayed inhibitory properties in multiple kindling models, for example, in the fully kindled state and in some cases during the kindling development. In addition, retigabine was effective in preventing status epilepticus seizures in rodents with cobalt-induced epileptogenic lesions, and inhibiting tonic extensor seizures in genetically susceptible mice. The relevance of these models to human epilepsy, however, is not known.

Pharmacodynamic effects

In rats, retigabine increased the sleep time induced by thiopental sodium from approximately 4 min to 53 min, and the propofol-induced sleep time from approximately 8 min to 12 min. There was no effect on sleep time induced by halothane or methohexital sodium. Retigabine may increase the duration of anaesthesia induced by some anaesthetics (for example thiopental sodium).

Absorption

After both single and multiple oral doses, retigabine is rapidly absorbed with median t_max values generally between 0.5 and 2 hours. Absolute oral bioavailability of retigabine relative to an intravenous dose is approximately 60%.

Administration of retigabine with a high fat meal resulted in no change in the overall extent of retigabine absorption, but food reduced the between-subject variability in C_max (23%) compared to the fasted state (41%), and led to an increase in C_max (38%). The effect of food on C_max under usual clinical conditions is not expected to be clinically relevant. Therefore retigabine may be taken with or without food.

Distribution

Retigabine is approximately 80% bound to plasma protein over the concentration range of 0.1 to 2 µg/ml. The steady state volume of distribution of retigabine is 2 to 3 l/kg following intravenous dosing.

Biotransformation

Retigabine is extensively metabolised in humans. A substantial fraction of the retigabine dose is converted to inactive N-glucuronides. Retigabine is also metabolised to an N-acetyl metabolite (NAMR) that is also subsequently glucuronidated. NAMR has antiepileptic activity, but is less potent than retigabine in animal seizure models.

There is no evidence for hepatic oxidative metabolism of retigabine or NAMR by cytochrome P450 enzymes. Therefore, co-administration with inhibitors or inducers of cytochrome P450 enzymes is unlikely to affect the pharmacokinetics of retigabine or NAMR.

In vitro studies using human liver microsomes showed little or no potential for retigabine to inhibit the major cytochrome P450 isoenzymes (including CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4/5). In addition, retigabine and NAMR did not induce CYP1A2 or CYP3A4/5 in human primary hepatocytes. Therefore, retigabine is unlikely to affect the pharmacokinetics of substrates of the major cytochrome P450 isoenzymes through inhibition or induction mechanisms.

Elimination

Elimination of retigabine occurs via a combination of hepatic metabolism and renal excretion. A total of approximately 84% of the dose is recovered in the urine, including the N-acetyl metabolite (18%), N-glucuronides of the parent active substance and of the N-acetyl metabolite (24%), or parent active substance (36%). Only 14% of retigabine is excreted in the faeces. Retigabine has a plasma half-life of approximately 6 to 10 hours. The total clearance of retigabine from plasma following intravenous dosing is typically 0.4 to 0.6 l/h/kg.

Linearity

Retigabine pharmacokinetics are essentially linear over the single-dose range of 25 to 600 mg in healthy volunteers and up to 1,200 mg daily in patients with epilepsy, with no unexpected accumulation following repeated administration.

Special patient populations

Renal impairment

In a single-dose study, retigabine AUC was increased by approximately 30% in volunteers with mild renal impairment (creatinine clearance 50 to 80 ml/min) and by approximately 100% in volunteers with moderate to severe renal impairment (creatinine clearance <50 ml/min), relative to healthy volunteers. Adjustment of the retigabine dose is recommended in patients with moderate to severe renal impairment but no adjustment of the retigabine dose is recommended in patients with mild renal impairment.

In a single-dose study in healthy volunteers and subjects with end stage renal disease, the retigabine AUC was increased by approximately 100% in the subjects with end stage renal disease relative to healthy volunteers.

In a second single-dose study in subjects with end stage renal disease receiving chronic haemodialysis (n= 8), initiation of dialysis at approximately 4 hours after a single dose of retigabine (100 mg) resulted in a median reduction in retigabine plasma concentrations of 52% from the start to end of dialysis. The percentage decrease in plasma concentration during dialysis ranged from 34% to 60% except for one subject who had a 17% reduction.

Hepatic impairment

In a single-dose study, there were no clinically significant effects on retigabine AUC in volunteers with mild hepatic impairment (Child-Pugh score 5 to 6). The retigabine AUC was increased by approximately 50% in volunteers with moderate hepatic impairment (Child-Pugh score 7 to 9) and by approximately 100% in volunteers with severe hepatic impairment (Child-Pugh score >9), relative to healthy volunteers. Adjustment of the retigabine dose is recommended in patients with moderate or severe hepatic impairment.

Body weight

In a population pharmacokinetic analysis, retigabine clearance increased with increasing body surface area. However, this increase is not considered to be clinically meaningful, and since retigabine is titrated according to individual patient response and tolerability, dose-adjustments are not required on the basis of body weight.

Elderly (65 years of age and above)

In a single-dose study, retigabine was eliminated more slowly by healthy elderly volunteers (66 to 82 years of age) relative to healthy young adult volunteers, resulting in a higher AUC (approximately 40 to 50%) and longer terminal half-life (30%).

Gender

The results of a single-dose study showed that in young adult volunteers, retigabine C_max was approximately 65% higher in females than in males, and in elderly volunteers (66 to 82 years of age), retigabine C_max was approximately 75% higher in females compared with males. When C_max was normalized for weight, the values were approximately 30% higher in young females than in males and 40% higher in elderly females compared with males. However, there was no apparent gender difference in weight-normalized clearance, and since retigabine is titrated according to individual patient response and tolerability, dose-adjustments are not required on the basis of gender.

Race

A post-hoc analysis across multiple healthy volunteer studies demonstrated a 20% reduction in retigabine clearance in healthy black volunteers relative to healthy Caucasian volunteers. However, this effect is not considered clinically significant, therefore no adjustment of the retigabine dose is recommended.

Paediatric population

The pharmacokinetics of retigabine in children below 12 years of age have not been investigated.

An open-label, multiple dose pharmacokinetic, safety and tolerability study in five subjects aged between 12 years to less than 18 years with partial onset seizures determined that the pharmacokinetics of retigabine in adolescents were consistent with the pharmacokinetics of retigabine in adults. However, efficacy and safety of retigabine have not been determined in adolescents.

Maximum doses in repeat dose toxicity studies were limited by the exaggerated pharmacologic effects of retigabine (including ataxia, hypokinesia and tremor). At no observed effect levels, animal exposure in these studies was generally less than that reached in humans at recommended clinical doses.

Distension of the gall bladder was seen in studies with dogs, but there was no evidence of cholestasis or other signs of gall bladder dysfunction, and bile ejection volume was unchanged. The gall bladder distension in the dog resulted in focal compression of the liver. No signs of gall bladder dysfunction were seen clinically.

Non-clinical data reveal no special hazard for humans based on studies of genotoxicity or carcinogenic potential.

Reproductive toxicology

Retigabine had no effect on fertility or general reproductive performance.

In rats, retigabine and/or its metabolites crossed the placenta resulting in tissue concentrations that were similar in dams and foetuses.

There was no evidence of teratogenicity following administration of retigabine to pregnant animals during the period of organogenesis. In a study of peri- and post-natal development in rats, retigabine was associated with increased perinatal mortality following administration during pregnancy. In addition, there was a delay in auditory startle response development. These findings were apparent at exposure levels lower than those obtained with clinically recommended doses and were accompanied by maternal toxicities (including ataxia, hypokinesia, tremor and reduced body weight gain). The maternal toxicities interfered with higher dosing of the dams and hence deduction of safety margins with regard to human therapy.