Safety, Tolerability and Pharmacokinetics of Single and Repeat Doses of Vixotrigine in Healthy Volunteers

Neuropathic pain affects ~ 6.9–10% of the general population and leads to loss of function, anxiety, depression, sleep disturbance, and impaired cognition. Here, we report the safety, tolerability, and pharmacokinetics of a voltage‐dependent and use‐dependent sodium channel blocker, vixotrigine, currently under investigation for the treatment of neuropathic pain conditions. The randomized, placebo‐controlled, phase I clinical trials were split into single ascending dose (SAD) and multiple ascending dose (MAD) studies. Healthy volunteers received oral vixotrigine as either single doses followed by a ≥ 7‐day washout period for up to 5 dosing sessions (SAD, n  = 30), or repeat doses (once or twice daily) for 14 and 28 days (MAD, n  = 51). Adverse events (AEs), maximum observed vixotrigine plasma concentration (C max ), area under the concentration‐time curve from predose to 24 hours postdose (AUC 0–24 ), time to C max (T max ), and terminal half‐life ( t 1/2) , among others, were assessed. Drug‐related AEs were reported in 47% and 53% of volunteers in the SAD and MAD studies, respectively, with dizziness as the most commonly reported drug‐related AE. SAD results showed that C max and AUC increased with dose, T max was 1–2 hours, and t 1/2 was ~ 11 hours. A twofold increase in accumulation was observed when vixotrigine was taken twice vs. once daily (MAD). Steady‐state was achieved from day 5 onward. These data indicate that oral vixotrigine is well‐tolerated when administered as single doses up to 825 mg and multiple doses up to 450 mg twice daily.