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

Figures & data

Table 1 Comparison of NAMR C_max in clinical trials and ratio to in vitro resultsa

NAMR Cmax (mean [SD]), estimated from Population PK analysis
EZG/RTG daily dose (subjects, n)	600 mg (668)	900 mg (632)	1200 mg (546)
NAMR Cmax ng/mL	595 (184)	809 (250)	1027 (344)
Ratio NAMR Cmax/2730b	0.22	0.30	0.38

Notes:

a Valeant Pharmaceuticals International Study PR2008-017, data on file, 2008

b 2,730=10 μM represents approximate 50% inhibition.

Abbreviations: C_max, maximum observed concentration; EZG, ezogabine; NAMR, N-acetyl metabolite of EZG/RTG; PK, pharmacokinetic; RTG, retigabine; SD, standard deviation.

Figure 1 Study design of digoxin and EZG/RTG up-titration.

Abbreviations: EZG, ezogabine; PK, pharmacokinetics; RTG, retigabine.

Table 2 Summary of digoxin pharmacokinetic parameters

	Session 1 (digoxin alone)	Session 2 (digoxin + EZG/RTG)
EZG/RTG dose	0 mg (n=29)	600 mg (n=28)	900 mg (n=24)	1,050 mg (n=5)	1,200 mg (n=18)
Digoxin plasma PK parameters
AUC0–120 (ng ·h/mL)	12.53 (26.89)	13.54 (27.47)	14.39 (20.54)	13.42 (17.13)	13.96 (28.38)
AUC0–48 (ng ·h/mL)	8.43 (25.36)	9.30 (27.96)	9.78 (21.38)	8.62 (19.74)	9.25 (27.66)
Cmax (ng/mL)	0.76 (36.94)	0.89 (36.67)	0.83 (30.71)	0.67 (24.29)	0.78 (40.41)
Tmax (h) median (range)	1.00 (0.50–3.00)	1.00 (0.50–2.00)	1.00 (0.50–2.00)	0.50 (0.50–1.00)	1.00 (0.50–3.00)
Digoxin urinary PK parameters
Ae0–48 (ng)	67,289 (33)	62,309 (24)	77,612 (25)	65,451 (30)	68,771 (32)
Clearance (L/h)	7.98 (26.62)	6.70 (21.69)	7.94 (23.21)	7.59 (32.30)	7.44 (23.93)

Notes: Data are presented as geometric mean between-subject coefficient of variation (CVb%), based on the log_e-transformed data. The data from one 51-year-old male subject were excluded from the statistical analyses owing to extremely low digoxin plasma concentration at the baseline assessment (AUC_0–48 0.75 ng ·h/mL). However, the three digoxin AUC_0–48 values for this subject with co-administration of EZG/RTG were comparable with the rest of the study population: 7.29 ng ·h/mL (600 mg EZG/RTG), 7.81 ng ·h/mL (900 mg EZG/RTG), and 5.82 ng · h/mL (1,050/1,200 mg EZG/RTG).

Abbreviations: Ae_0–48, urinary recovery of unchanged drug from 0 to 48 hours; AUC, area under the concentration–time curve; C_max, maximum observed concentration; EZG, ezogabine; PK, pharmacokinetic; RTG, retigabine; T_max, time to C_max.

Figure 2 Plasma AUC_0–120 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.

Table 3 Summary of statistical analysis assessing the effect of EZG/RTGNAMRon the pharmacokinetics of digoxin

PK parameter	EZG/RTG + digoxin vs digoxin alone (EZG/RTG dose)	Geometric least squares mean		Ratio (90% CI)
		Digoxin + EZG/RTG	Digoxin alone
AUC0–120	600 mg	13.54	12.52	1.08 (1.01–1.15)
	900 mg	14.80	12.52	1.18 (1.10–1.27)
	1,050/1,200 mg combined	14.15	12.52	1.13 (1.05–1.21)
	1,050 mg	13.42	10.79	1.24 (1.01–1.54)
	1,200 mg	13.96	12.63	1.11 (1.02–1.20)
Cmax	600 mg	0.89	0.75	1.18 (1.05–1.31)
	900 mg	0.86	0.75	1.15 (1.02–1.29)
	1,050/1,200 mg combined	0.78	0.75	1.04 (0.92–1.16)
	1,050 mg	0.67	0.59	1.14 (0.90–1.44)
	1,200 mg	0.78	0.75	1.03 (0.89–1.20)
CLr	600 mg	6.70	8.05	0.83 (0.78–0.89)
	900 mg	7.96	8.05	0.99 (0.92–1.06)
	1,050/1,200 mg combined	7.46	8.05	0.93 (0.86–1.00)
	1,050 mg	7.59	7.69	0.99 (0.88–1.11)
	1,200 mg	7.44	7.98	0.93 (0.85–1.02)

Notes: The number of subjects included in the statistical analysis was 28 for the 600 mg EZG/RTG dose, 24 for the 900 mg dose, 23 for the combined 1,050/1,200 mg dose, 5 for the 1,050 mg EZG/RTG dose and 18 for the 1,200 mg dose.

Abbreviations: AUC, area under the concentration–time curve; C_max, maximum observed concentration; CI, confidence interval; CLr, renal clearance; EZG, ezogabine; NAMR, N-acetyl metabolite of EZG/RTG; PK, pharmacokinetic; RTG, retigabine.

Table 4 Summary of the most frequent adverse events (affecting ≥20% of participants during the entire study; safety population)

System organ class preferred term	Session 1 (digoxin only) (n=30)	Session 2 (digoxin and EZG/RTG) (n=29)	Total safety population (N=30)
Any AE	4 (13)	28 (97)	29 (97)
AE resulting in withdrawal	1 (3)	7 (24)	8 (27)
Nervous system disordersa	2 (7)	25 (86)	25 (83)
Somnolence	2 (7)	17 (59)	18 (60)
Dizziness	0	17 (59)	17 (57)
Headache	0	16 (55)	16 (53)
Memory impairment	0	7 (24)	7 (23)
Paresthesia	0	6 (21)	6 (20)
Gastrointestinal system disordersa	2 (7)	22 (76)	22 (73)
Dyspepsia	2 (7)	6 (21)	8 (27)
Constipation	0	7 (24)	7 (23)
Abdominal pain	0	6 (21)	6 (20)
Dry mouth	0	6 (21)	6 (20)
Psychiatric disordersa	0	21 (72)	21 (70)
Euphoric mood	0	14 (48)	14 (47)
Confusional state	0	13 (45)	13 (43)
Hallucination	0	11 (38)	11 (37)
Musculoskeletal and connective disordersa	1 (3)	13 (45)	14 (47)
Muscle twitching	0	9 (31)	9 (30)
Myalgia	1 (3)	5 (17)	6 (20)
General disorders and administration-site conditionsa	1 (3)	8 (28)	9 (30)
Fatigue	1 (3)	5 (17)	6 (20)
Respiratory, thoracic, and mediastinal disordersa	0	9 (31)	9 (30)
Skin and subcutaneous tissue disordersa	1 (3)	8 (28)	9 (30)
Metabolism and nutrition disordersa	0	7 (24)	7 (23)
Eye disordersa	0	6 (21)	6 (20)
Vision blurred	0	6 (21)	6 (20)

Notes: Data are presented as numbers of individuals experiencing the event (%); coded under MedDRA Version 15.0.

a Any AE.

Abbreviations: AE, adverse event; EZG, ezogabine; RTG, retigabine.

Figure S1A NAMR AUC_0–8 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 AUC_0–8 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.