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

Abstract

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 concentrationtime curve from predose to 24 hours postdose (AUC 0-24 ), time to C max (T max ), and terminal half-life (t1/2), 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.Neuropathic pain can arise from a lesion or disease of the somatosensory system, including peripheral fibers (Aβ, Aδ, and C fibers) and central neurons. 1 The signs and symptoms of neuropathic pain include allodynia, spontaneous paroxysmal pain, hyperalgesia, and, on occasion, causalgia or incessant burning pain. 2 The estimated prevalence of neuropathic pain in the general population is 6.9-10%. 3 Substantial impairment of quality of life is caused due to loss of function, anxiety, depression, sleep disturbance, and impaired cognition. 1 Voltage-gated sodium channels (Navs) are complex transmembrane proteins responsible for the initiation and propagation of action potentials in neurons. 4 Gain-offunction changes produced by missense substitutions in the genes encoding Nav1.7-1.9 have been implicated in human pain syndromes through genetic studies. 5,6 Loss-of-function autosomal recessive mutations in the gene encoding the α-subunit of Nav1.7 result in congenital insensitivity to pain. 5,7 Sodium channel subtype Nav1.7 is expressed in peripheral sensory neurons innervating skin, viscera, and dorsal

Efficacy and safety of vixotrigine in idiopathic or diabetes-associated painful small fibre neuropathy (CONVEY): a phase 2 placebo-controlled enriched-enrolment randomised withdrawal study

“…The safety profile in the OL period and lack of withdrawal syndrome following abrupt discontinuation of dosing were consistent with that observed in previous studies of vixotrigine. 14 , 15 We also observed a significant reduction in ADP scores with vixotrigine compared with placebo, despite having a smaller sample size than planned, suggesting that vixotrigine is indeed effective.…”

“…Vixotrigine doses of 200 mg twice daily (BID) and 350 mg BID were selected as they were predicted to maintain mean trough plasma concentrations above 1.12 μg/mL and 1.96 μg/mL, respectively, which was predicted to provide therapeutic effects in participants with painful SFN, based on preclinical findings. Based on clinical trial data, vixotrigine was well tolerated with repeat dosing up to 450 mg BID in healthy individuals; the BID dosing interval in the present study was determined based on a terminal half-life of 7.2–12.7 h. 15 CONVEY was designed to evaluate the efficacy and safety of vixotrigine in patients with idiopathic or diabetes-associated painful SFN.…”