Measuring muscle velocity recovery cycles (MVRCs) is a method to obtain information on muscle cell excitability, independent of neuromuscular transmission. The goal was to validate MVRC as a... Show moreMeasuring muscle velocity recovery cycles (MVRCs) is a method to obtain information on muscle cell excitability, independent of neuromuscular transmission. The goal was to validate MVRC as a pharmacodynamic (PD) biomarker for drugs targeting muscle excitability. As proof-of-concept, sensitivity of MVRC to detect effects of mexiletine, a voltage-gated sodium channel (Na-v) blocker, was assessed. In a randomized, double-blind, two-way crossover study, effects of a single pharmacologically active oral dose of 333 mg mexiletine was compared to placebo in 15 healthy male subjects. MVRC was performed predose, and 3- and 5-h postdose using QTrac. Effects of mexiletine versus placebo were calculated using a mixed effects model with baseline as covariate. Mexiletine had significant effects on MVRC when compared to placebo. Early supernormality after five conditioning stimuli was decreased by mexiletine (estimated difference -2.78% [95% confidence interval: -4.16, -1.40]; p value = 0.0003). Moreover, mexiletine decreased the difference in late supernormality after five versus one conditioning stimuli (5XLSN; ED -1.46% [-2.26, -0.65]; p = 0.001). These results indicate that mexiletine decreases the percentage increase in velocity of the muscle fiber action potential after five conditioning stimuli, at long and short interstimulus intervals, which corresponds to a decrease in muscle membrane excitability. This is in line with the pharmacological activity of mexiletine, which leads to use-dependent Na(V)1.4 blockade affecting muscle membrane potentials. This study shows that effects of mexiletine can be detected using MVRC in healthy subjects, thereby indicating that MVRC can be used as a tool to demonstrate PD effects of drugs targeting muscle excitability in early phase drug development. Show less
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... Show moreSelective 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 (TEd(40) (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. Show less
