Effect of lacosamide on the steady-state pharmacokinetics of digoxin: results
from a phase I, multiple-dose, double-blind, randomised, placebo-controlled,
crossover trial.
Author(s): Cawello W(1), Mueller-Voessing C, Andreas JO.
Affiliation(s): Author information:
(1)UCB Biosciences GmbH, UCB Pharma, Global Statistical Sciences,
Alfred-Nobel-Str. 10, 40789, Monheim am Rhein, Germany, Willi.Cawello@ucb.com.
Publication date & source: 2014, Clin Drug Investig. , 34(5):327-34
BACKGROUND: Recent data suggest that P-glycoprotein may be involved in cellular
transport of lacosamide.
OBJECTIVE: To investigate potential drug-drug interactions (DDIs) between
lacosamide and digoxin, this phase I, multiple-dose, randomised, double-blind,
placebo-controlled, crossover trial assessed the pharmacokinetics,
pharmacodynamics, safety and tolerability of digoxin administered in combination
with lacosamide or placebo.
METHODS: Twenty healthy White male volunteers were randomised. After receiving
digoxin 0.25 mg three times daily on day 1 (loading dose), participants received
digoxin 0.25 mg once daily on days 2-22. Participants received either lacosamide
(200 mg twice daily) or placebo on days 8-11 and vice versa on days 18-21, after
a 6-day washout. The steady-state area under concentration-time curve over the
dosing interval (AUC(24,ss)) and maximum steady-state plasma concentration
(C(max,ss)) of digoxin were measured; ratios of these parameters for
co-administration of digoxin + lacosamide versus digoxin alone were used to
evaluate potential DDIs. Interaction was excluded if the 90 % confidence interval
(CI) for the geometric mean ratio of AUC24,ss and C max,ss fell within the
acceptance range for bioequivalence (0.8-1.25).
RESULTS: The point estimates (90 % CI) of the geometric mean ratios for
co-administration of digoxin with lacosamide versus digoxin alone for AUC(24,ss)
[1.024 (0.979-1.071)] and C(max,ss) [1.049 (0.959-1.147)] were within the
acceptance range for bioequivalence. Digoxin and lacosamide co-administration was
generally well-tolerated. A small numerical increase in the mean PR interval
following co-administered digoxin + lacosamide was observed versus digoxin alone
and versus pre-treatment baseline values (178.5 vs. 170.4 or 166.8 ms,
respectively). The RR interval increased in parallel. The change was not
considered clinically relevant.
CONCLUSION: Co-administration of steady-state digoxin (0.25 mg/day) with
multiple-dose lacosamide (400 mg/day) versus digoxin alone revealed no
differences in digoxin disposition.
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