Clinical pharmacokinetics of retigabine/ezogabine.
BACKGROUND
Retigabine is an antiepileptic drug that reduces neuronal excitability by enhancing potassium channel activity.


METHODS
This manuscript summarizes the pharmacokinetic and biopharmaceutical properties of retigabine collated from published and unpublished in vitro and clinical phase I-III studies in healthy volunteers or patients with partial-onset seizures.


RESULTS
Retigabine is rapidly absorbed with a median time to C(max) of 0.5-2.0 hours. Thereafter, plasma concentrations decline in a mono-exponential manner, with a median half-life of 6-8 hours. The absolute oral bioavailability of retigabine is ~60%. Retigabine is metabolized extensively by N-acetylation and subsequent N-glucuronidation. In vitro and in vivo studies have shown that the drug-interaction potential of retigabine is low. The pharmacokinetics of retigabine are linear over the dose range 200-400mg three times daily (tid), with ~ 35-50% between-subject variability. Systemic exposure was not affected by a high fat meal, but C(max) was, ~14% and ~38% higher in the fed versus fasted state for the 200 and 400mg tablets, respectively. Retigabine drug-related material is primarily eliminated renally with unchanged retigabine accounting for ~36%. Retigabine plasma clearance decreased as severity of renal or hepatic impairment increased. Systemic exposure to retigabine is unaffected by gender when normalized for body weight. In elderly patients, retigabine systemic exposure was higher, and half-life was longer than in younger patients.


CONCLUSIONS
Retigabine should be administered tid without regard to food. No adjustments required for gender, race, or genetic/polymorphisms. Dosage adjustments are recommended in elderly patients and those with moderate and severe renal or moderate hepatic impairment.
GlaxoSmithKline, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK. debra.j.tompson@gsk.com.
Debra J
DJ
Tompson
Christopher S
CS
Crean
D000367:Age Factors; D000368:Aged; D000927:Anticonvulsants / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001682:Biological Availability; D002219:Carbamates / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D002986:Clinical Trials as Topic; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004828:Epilepsies, Partial / Q000188:drug therapy*; D006207:Half-Life; D006801:Humans; D008107:Liver Diseases / Q000503:physiopathology; D010655:Phenylenediamines / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D051437:Renal Insufficiency / Q000503:physiopathology
D000927:Anticonvulsants; D002219:Carbamates; D010655:Phenylenediamines; C101866:ezogabine