HP58 : Effects of sodium channel blockers on “nerve exciatability threshold tracking“

Abstract

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 using nerve excitability threshold tracking in 18 healthy subjects. In a randomized, double-blind, three-way crossover study, effects of single doses of mexiletine and lacosamide were compared to placebo. On each study visit, motor- and sensory nerve excitability measurements of the median nerve were performed (pre-dose; 2- and 5-hours post-dose). Stimulation was guided by QTRAC-S. Treatment effects were calculated using an ANCOVA, with baseline as covariate. Mexiletine and lacosamide had significant effects on a multitude of motor- and sensory nerve excitability parameters. In motor nerves, TEd 40-60ms was significantly decreased when compared to placebo, with an estimated difference -1.37% (95%CI:-2.20,-0.55;p=0.002) after mexiletine and -1.27% (95%CI:-2.0968,-0.4430; p=0.004) after lacosamide. Moreover, mexiletine and lacosamide significantly increased superexcitability in motor nerves, with an estimated difference of 1.74% (95%CI:0.61,2.87; p=0.004) and 1.47% (95%CI:0.34, 2.60;p=0.013), respectively. The strength-duration time constant decreased after lacosamide in both motor nerves -0.03ms (95%CI:-0.06,-0.01;p=0.005) and sensory nerves -0.08ms (95%CI:-0.12,-0.05;p<0.001). Mexiletine and lacosamide significantly decrease excitability of motor and sensory nerves, in line with the mechanism of action. This study shows that threshold tracking can be an effective biomarker in pharmacological studies. The method would therefore be a valuable tool in drug development, to help identifying target engagement in healthy subjects.