Lack of effect of ezogabine/retigabine on the pharmacokinetics of digoxin in healthy individuals: results from a drug–drug interaction study

Lack of effect of ezogabine/retigabine on the pharmacokinetics of digoxin in healthy individuals: results from a drug–drug interaction study

Debra J Tompson,1 Christopher S Crean,2 Mauro Buraglio,1 Thangam Arumugham3 1Clinical Pharmacology Modelling and Simulation, GlaxoSmithKline, Stevenage, Hertfordshire, UK; 2Clinical Pharmacology and Pharmacokinetics, Valeant Pharmaceuticals North America, Durham, NC, USA; 3Clinical Statistics, Glax...

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Autores principales: Tompson DJ, Crean CS, Buraglio M, Arumugham T
Formato: article
Lenguaje:EN
Publicado: Dove Medical Press 2014
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Therapeutics. Pharmacology
RM1-950
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spelling oai:doaj.org-article:a39ebd84ab9c42aa8ea85e3337382a262021-12-02T00:45:39ZLack of effect of ezogabine/retigabine on the pharmacokinetics of digoxin in healthy individuals: results from a drug–drug interaction study1179-1438https://doaj.org/article/a39ebd84ab9c42aa8ea85e3337382a262014-10-01T00:00:00Zhttp://www.dovepress.com/lack-of-effect-of-ezogabineretigabine-on-the-pharmacokinetics-of-digox-peer-reviewed-article-CPAAhttps://doaj.org/toc/1179-1438 Debra J Tompson,1 Christopher S Crean,2 Mauro Buraglio,1 Thangam Arumugham3 1Clinical Pharmacology Modelling and Simulation, GlaxoSmithKline, Stevenage, Hertfordshire, UK; 2Clinical Pharmacology and Pharmacokinetics, Valeant Pharmaceuticals North America, Durham, NC, USA; 3Clinical Statistics, GlaxoSmithKline, Raleigh-Durham, NC, USA 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. Keywords: digoxin, retigabine, ezogabine, drug–drug interactionsTompson DJCrean CSBuraglio MArumugham TDove Medical PressarticleTherapeutics. PharmacologyRM1-950ENClinical Pharmacology: Advances and Applications, Vol 2014, Iss default, Pp 149-159 (2014)
institution DOAJ
collection DOAJ
language EN
topic Therapeutics. Pharmacology
RM1-950
spellingShingle Therapeutics. Pharmacology
RM1-950
Tompson DJ
Crean CS
Buraglio M
Arumugham T
Lack of effect of ezogabine/retigabine on the pharmacokinetics of digoxin in healthy individuals: results from a drug–drug interaction study
description Debra J Tompson,1 Christopher S Crean,2 Mauro Buraglio,1 Thangam Arumugham3 1Clinical Pharmacology Modelling and Simulation, GlaxoSmithKline, Stevenage, Hertfordshire, UK; 2Clinical Pharmacology and Pharmacokinetics, Valeant Pharmaceuticals North America, Durham, NC, USA; 3Clinical Statistics, GlaxoSmithKline, Raleigh-Durham, NC, USA 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. Keywords: digoxin, retigabine, ezogabine, drug–drug interactions
format article
author Tompson DJ
Crean CS
Buraglio M
Arumugham T
author_facet Tompson DJ
Crean CS
Buraglio M
Arumugham T
author_sort Tompson DJ
title Lack of effect of ezogabine/retigabine on the pharmacokinetics of digoxin in healthy individuals: results from a drug–drug interaction study
title_short Lack of effect of ezogabine/retigabine on the pharmacokinetics of digoxin in healthy individuals: results from a drug–drug interaction study
title_full Lack of effect of ezogabine/retigabine on the pharmacokinetics of digoxin in healthy individuals: results from a drug–drug interaction study
title_fullStr Lack of effect of ezogabine/retigabine on the pharmacokinetics of digoxin in healthy individuals: results from a drug–drug interaction study
title_full_unstemmed Lack of effect of ezogabine/retigabine on the pharmacokinetics of digoxin in healthy individuals: results from a drug–drug interaction study
title_sort lack of effect of ezogabine/retigabine on the pharmacokinetics of digoxin in healthy individuals: results from a drug–drug interaction study
publisher Dove Medical Press
publishDate 2014
url https://doaj.org/article/a39ebd84ab9c42aa8ea85e3337382a26
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