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

Tompson DJ, Crean CS, Buraglio M, Arumugham T - Clin Pharmacol (2014)

Bottom Line: EZG/RTG did not inhibit P-gp.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.

View Article: PubMed Central - PubMed

Affiliation: Clinical Pharmacology Modelling and Simulation, GlaxoSmithKline, Stevenage, Hertfordshire, UK.

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.

No MeSH data available.


Related in: MedlinePlus

Plasma AUC0–120 and renal clearance.Notes: Ratio of geometric means and 90% CI of digoxin co-administered with EZG/RTG 600, 900, and 1,050/1,200 mg/day versus digoxin alone. 600 mg (n=28); 900 mg (n=24); and 1,050 mg (n=5)/1,200 mg (n=18). Data labels given as ratio of geometric means (90% CI). Dotted lines represent the lower and upper limits for bioequivalence (0.80–1.25). Subjects receiving the 1,050 mg and 1,200 mg doses were combined.Abbreviations: AUC, area under concentration–time curve; CI, confidence interval; EZG, ezogabine; PK, pharmacokinetics; RTG, retigabine.
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f2-cpaa-6-149: Plasma AUC0–120 and renal clearance.Notes: Ratio of geometric means and 90% CI of digoxin co-administered with EZG/RTG 600, 900, and 1,050/1,200 mg/day versus digoxin alone. 600 mg (n=28); 900 mg (n=24); and 1,050 mg (n=5)/1,200 mg (n=18). Data labels given as ratio of geometric means (90% CI). Dotted lines represent the lower and upper limits for bioequivalence (0.80–1.25). Subjects receiving the 1,050 mg and 1,200 mg doses were combined.Abbreviations: AUC, area under concentration–time curve; CI, confidence interval; EZG, ezogabine; PK, pharmacokinetics; RTG, retigabine.

Mentions: Compared with administration of digoxin alone (session 1), co-administration with EZG/RTG at doses of 600, 900, and 1,050/1,200 mg/day led to small, non-dose-dependent increases in the range of 8%–18% in the digoxin AUC0–120 and a range of 1%–17% decrease in renal clearance (Figure 2). The 90% CIs for the AUC0–120 ratios of 600 mg and 1,050/1,200 mg/day EZG/RTG + digoxin doses versus digoxin alone fell within the 90% CI range associated with bioequivalence (0.80–1.25) (Table 3). However, for the 900 mg/day dose of EZG/RTG, the lower end of the 90% CI fell just outside the bioequivalence range.


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

Tompson DJ, Crean CS, Buraglio M, Arumugham T - Clin Pharmacol (2014)

Plasma AUC0–120 and renal clearance.Notes: Ratio of geometric means and 90% CI of digoxin co-administered with EZG/RTG 600, 900, and 1,050/1,200 mg/day versus digoxin alone. 600 mg (n=28); 900 mg (n=24); and 1,050 mg (n=5)/1,200 mg (n=18). Data labels given as ratio of geometric means (90% CI). Dotted lines represent the lower and upper limits for bioequivalence (0.80–1.25). Subjects receiving the 1,050 mg and 1,200 mg doses were combined.Abbreviations: AUC, area under concentration–time curve; CI, confidence interval; EZG, ezogabine; PK, pharmacokinetics; RTG, retigabine.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4206209&req=5

f2-cpaa-6-149: Plasma AUC0–120 and renal clearance.Notes: Ratio of geometric means and 90% CI of digoxin co-administered with EZG/RTG 600, 900, and 1,050/1,200 mg/day versus digoxin alone. 600 mg (n=28); 900 mg (n=24); and 1,050 mg (n=5)/1,200 mg (n=18). Data labels given as ratio of geometric means (90% CI). Dotted lines represent the lower and upper limits for bioequivalence (0.80–1.25). Subjects receiving the 1,050 mg and 1,200 mg doses were combined.Abbreviations: AUC, area under concentration–time curve; CI, confidence interval; EZG, ezogabine; PK, pharmacokinetics; RTG, retigabine.
Mentions: Compared with administration of digoxin alone (session 1), co-administration with EZG/RTG at doses of 600, 900, and 1,050/1,200 mg/day led to small, non-dose-dependent increases in the range of 8%–18% in the digoxin AUC0–120 and a range of 1%–17% decrease in renal clearance (Figure 2). The 90% CIs for the AUC0–120 ratios of 600 mg and 1,050/1,200 mg/day EZG/RTG + digoxin doses versus digoxin alone fell within the 90% CI range associated with bioequivalence (0.80–1.25) (Table 3). However, for the 900 mg/day dose of EZG/RTG, the lower end of the 90% CI fell just outside the bioequivalence range.

Bottom Line: EZG/RTG did not inhibit P-gp.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.

View Article: PubMed Central - PubMed

Affiliation: Clinical Pharmacology Modelling and Simulation, GlaxoSmithKline, Stevenage, Hertfordshire, UK.

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.

No MeSH data available.


Related in: MedlinePlus