TY  - JOUR
TI  - Effects of mexiletine and lacosamide on nerve excitability in healthy subjects: a randomized, double-blind, placebo-controlled, crossover study
UR  - https://doi.org/10.1002/cpt.2694
SP  - 1008
VL  - 112
PB  - Wiley
A1  - Ruijs, Titia Q
A1  - Koopmans, Ingrid W
A1  - de Kam, Marieke L
A1  - van Esdonk, Michiel J
A1  - Koltzenburg, Martin
A1  - Groeneveld, Geert Jan
A1  - Heuberger, Jules AAC
Y1  - 2022/07/19/
IS  - 5
N2  - Selective voltage-gated sodium channel blockers are of growing interest as treatment for pain. For drug development of such compounds, it would be critical to have a biomarker that can be used for proof-of-mechanism. We aimed to evaluate whether drug-induced changes in sodium conductance can be detected in the peripheral nerve excitability profile in 18 healthy subjects. In a randomized, double-blind, 3-way crossover study, effects of single oral doses of 333?mg mexiletine and 300?mg lacosamide were compared with placebo. On each study visit, motor and sensory nerve excitability measurements of the median nerve were performed (predose; and 3 and 6 hours postdose) using Qtrac. Treatment effects were calculated using an analysis of covariance (ANCOVA) with baseline as covariate. Mexiletine and lacosamide had significant effects on multiple motor and sensory nerve excitability variables. Depolarizing threshold electrotonus (TEd40 (40?60?ms)) decreased by mexiletine (estimated difference (ED) ?1.37% (95% confidence interval (CI): ?2.20, ?0.547; P = 0.002) and lacosamide (ED ?1.27%, 95% CI: ?2.10, ?0.443; P = 0.004) in motor nerves. Moreover, mexiletine and lacosamide decreased superexcitability (less negative) in motor nerves (ED 1.74%, 95% CI: 0.615, 2.87; P = 0.004, and ED 1.47%, 95% CI: 0.341, 2.60; P = 0.013, respectively). Strength-duration time constant decreased after lacosamide in motor- (ED ?0.0342?ms, 95% CI: ?0.0571, ?0.0112; P = 0.005) and sensory nerves (ED ?0.0778?ms, 95% CI: ?0.116, ?0.0399; P?<?0.001). Mexiletine and lacosamide significantly decrease excitability of motor and sensory nerves, in line with their suggested mechanism of action. Results of this study indicate that nerve excitability threshold tracking can be an effective pharmacodynamic biomarker. The method could be a valuable tool in clinical drug development.
JF  - Clinical Pharmacology & Therapeutics
EP  - 1019
AV  - public
ID  - discovery10151845
N1  - This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. See: http://creativecommons.org/licenses/by-nc-nd/4.0/
ER  -