Abstract
Introduction
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.
Conclusion
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.
Supplementary materials
Figure S1A NAMR AUC0–8 versus digoxin AUC ratio.
Note: Each subject had multiple observations corresponding to the doses of EZG/RTG that they received in combination with digoxin.
Abbreviations: AUC, area under the concentration–time curve; EZG, ezogabine; NAMR, N-acetyl metabolite of EZG/RTG; RTG, retigabine.
Figure S1B NAMR AUC0–8 versus digoxin renal clearance ratio.
Note: Each subject had multiple observations corresponding to the doses of EZG/RTG that they received in combination with digoxin.
Abbreviations: AUC, area under the concentration–time curve; CLr, renal clearance; EZG, ezogabine; NAMR, N-acetyl metabolite of EZG/RTG; RTG, retigabine.
Acknowledgments
The authors would like to thank Ann Walker (from GSK), for contribution to the protocol development, and the Clinical Investigator, Dr Azra Hussaini (PAREXEL). Professional medical writing and editorial support was provided by Harry Law, BSc (Caudex Medical, Oxford, UK) and funded by Valeant Pharmaceuticals and GSK.
Disclosure
CSC is a consultant to Valeant Pharmaceuticals North America. DJT, MB, and TA are employees and shareholders of GlaxoSmithKline (GSK). The study was supported by Valeant Pharmaceuticals International and funded by GSK (study number RTG 11216). The authors have no further conflicts of interest in this work.