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Clinical Trial
. 2021 Jul;14(4):1272-1279.
doi: 10.1111/cts.12935. Epub 2020 Dec 13.

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

Himanshu Naik  1 , Deb J Steiner  1 , Mark Versavel  1   2 , Joanne Palmer  3 , Regan Fong  4
Affiliations
Clinical Trial

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

Himanshu Naik et al. Clin Transl Sci. 2021 Jul.

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 (Cmax ), area under the concentration-time curve from predose to 24 hours postdose (AUC0-24 ), time to Cmax (Tmax ), 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 Cmax and AUC increased with dose, Tmax was 1-2 hours, and t1/2 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.

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Conflict of interest statement

H.N. is an employee of and owns stock/stock options in Biogen. D.J.S. was previously the Biogen medical lead for vixotrigine and owns stock/stock options in Biogen. M.V. was a paid consultant to Biogen and Convergence Pharmaceuticals Ltd., a Biogen company, in relation to this study. J.P. was an employee of GlaxoSmithKline at the time of the study, and subsequently an employee of Convergence Pharmaceuticals Ltd., a Biogen company, and Biogen, and owned stock in Biogen and Convergence Pharmaceuticals Ltd. R.F. was an employee of GlaxoSmithKline at the time the study was conducted.

Figures

Figure 1
Figure 1
Systemic exposure of each vixotrigine dose in the single‐dose study for maximum observed concentration (Cmax) and area under the concentration‐time curve from predose extrapolated to infinite time (AUC0–inf).
Figure 2
Figure 2
Vixotrigine concentrations by time and dose in the single‐dose study.
Figure 3
Figure 3
Mean (SD) plasma vixotrigine linear concentration‐time plots in the repeat‐dose study.
See this image and copyright information in PMC

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