Muscle velocity recovery cycles as pharmacodynamic biomarker: Effects of mexiletine in a randomized double‐blind placebo‐controlled cross‐over study

Abstract

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 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 (Nav) 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 NaV1.4 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.

Safety, Pharmacokinetics, and Pharmacodynamics of a CLC-1 Inhibitor - A First-in-Class Compound That Enhances Muscle Excitability: A Phase I, Single- And Multiple-Ascending Dose Study

“…NMD670 (1200 mg) induced significant effects on MVRC variables. Previous work shows that MVRC can be used to detect acute pharmacological effects of drugs that modify muscle excitability 9 . The MVRC method was expected to be sensitive to inhibition of ClC-1 because effects of decreased ClC-1 function in patients with myotonia congenita can be demonstrated using MVRC 8 .…”

“…Measurements of muscle velocity recovery cycles (MVRC) were performed to evaluate PD effects of NMD670 7 8 . MVRC measurements were performed as described previously in the tibial muscle, using QTrac (recording protocol M3REC6, Institute of Neurology, London, UK) 9 . Recovery cycles with 1, 2, and 5 conditioning stimuli (CS), as well as frequency ramp, were recorded.…”