title: Lack of effect of ezogabine/retigabine on the pharmacokinetics of digoxin in healthy individuals: results from a drug-drug interaction study.
abstract: BACKGROUND
  The potential for ezogabine/retigabine (EZG/RTG) and its N-acetyl metabolite (NAMR) to inhibit the transporter protein P-glycoprotein-(P-gp)-mediated digoxin transport was tested in vitro. EZG/RTG did not inhibit P-gp. However, NAMR inhibited P-gp in a concentration-dependent manner. Based on these in vitro results, NAMR had the potential to inhibit P-gp at therapeutic doses of EZG/RTG (600-1,200 mg/day). As digoxin has a narrow therapeutic index, inhibition of digoxin clearance may have an impact on its safety.
  
  
  METHODS
  An open-label, single-center, two session, fixed-sequence study was conducted to assess the effect of co-administration of therapeutic doses of EZG/RTG on digoxin pharmacokinetics in healthy adults. In session 1, subjects received a single dose of digoxin 0.25 mg. In session 2, EZG/RTG was up-titrated over 6 weeks. Digoxin 0.25 mg was co-administered at EZG/RTG steady-state doses of 600, 900, and, based on tolerability, 1,050/1,200 mg/day. Blood samples were collected over 144 hours for determination of digoxin, EZG/RTG, and NAMR concentrations. Urine samples were collected over 48 hours for determination of digoxin concentrations.
  
  
  RESULTS
  Of 30 subjects enrolled, 29 were included in the pharmacokinetic analysis. Compared with digoxin alone, co-administration with EZG/RTG led to small increases in the digoxin plasma area under the concentration-time curve (AUC)0-120 at doses of 600, 900, and 1,050/1,200 mg (geometric mean ratio 1.08, 90% confidence interval [CI] 1.01-1.15; 1.18, 90% CI 1.10-1.27; 1.13, 90% CI 1.05-1.21, respectively). Safety was consistent with previous repeat-dose studies of EZG/RTG in healthy subjects.
  
  
  CONCLUSIONS
  Co-administration of EZG/RTG across the therapeutic range resulted in small, non-dose-dependent and non-clinically relevant increases in digoxin systemic exposure, suggesting that digoxin dose adjustment is not necessary.
authors.affiliation: Clinical Pharmacology Modelling and Simulation, GlaxoSmithKline, Stevenage, Hertfordshire, UK.
authors.forename: Debra J
authors.initials: DJ
authors.lastname: Tompson
authors.affiliation: Clinical Pharmacology and Pharmacokinetics, Valeant Pharmaceuticals North America, Durham, NC, USA.
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Crean
authors.affiliation: Clinical Pharmacology Modelling and Simulation, GlaxoSmithKline, Stevenage, Hertfordshire, UK.
authors.forename: Mauro
authors.initials: M
authors.lastname: Buraglio
authors.affiliation: Clinical Statistics, GlaxoSmithKline, Raleigh-Durham, NC, USA.
authors.forename: Thangam
authors.initials: T
authors.lastname: Arumugham
keywords: digoxin; drug–drug interactions; ezogabine; retigabine