A phase I, randomized, double‐blind, placebo‐controlled, single‐ and multiple dose escalation study evaluating the safety, pharmacokinetics and pharmacodynamics of VX‐128, a highly selective Nav1.8 inhibitor, in healthy adults

Clinical and Translational Science, vol. 15, pp. 981–993

Abstract

Abstract Selective inhibition of certain voltage‐gated sodium channels (Navs), such as Nav1.8, is of primary interest for pharmacological pain research and widely studied as a pharmacological target due to its contribution to repetitive firing, neuronal excitability, and pain chronification. VX‐128 is a highly potent and selective Nav1.8 inhibitor that was being developed as a treatment for pain. We evaluated the safety, tolerability, and pharmacokinetics of VX‐128 in healthy subjects in a single‐ and multiple‐ascending dose (MAD) first‐in‐human study. Pharmacodynamics were evaluated in the MAD part using a battery of evoked pain tests. Overall, single doses of VX‐128 up to 300 mg were well‐tolerated, although adverse effect (AE) incidence was higher in subjects receiving VX‐128 (41.7%) compared with placebo (25.0%). After multiple dosing of up to 10 days, skin rash events were observed at all dose levels (up to 100 mg once daily [q.d.]), in five of 26 (19.2%) subjects, including one subject receiving VX‐128 (100 mg q.d.) who had a serious AE of angioedema. A trend in pain tolerance were observed for cold pressor‐ and pressure pain, which was dose‐dependent for the latter. VX‐128 was rapidly absorbed (median time to maximum plasma concentration between 1 and 2 h) with a half‐life of ~80 h at 10 mg q.d., and approximately two‐fold accumulation ratio after 10 and 30 mg q.d. Although VX‐128, when given in a multiple dose fashion, resulted in early study termination due to tolerability issues, effects were observed on multiple pain tests that may support further investigation of Nav1.8 inhibitors as pain treatments.

Authors 4

1. Hemme J. Hijma Aachen Centre for Human Drug Research Leiden the Netherlands Centre for Human Drug Research (CHDR)

   Leiden University · Leiden University Medical Center · Centre for Human Drug Research

   Affiliation as printed

   Centre for Human Drug Research Leiden The Netherlands

   Leiden University Medical Centre Leiden The Netherlands

   Centre for Human Drug Research, Leiden, The Netherlands

   Leiden University Medical Centre, Leiden, The Netherlands

2. Emilie M.J. van Brummelen Aachen Centre for Human Drug Research Leiden the Netherlands Centre for Human Drug Research (CHDR)

   Centre for Human Drug Research

   Affiliation as printed

   Centre for Human Drug Research Leiden The Netherlands

   Centre for Human Drug Research, Leiden, The Netherlands

3. Pieter S. Siebenga Aachen Centre for Human Drug Research Leiden the Netherlands Centre for Human Drug Research (CHDR)

   Leiden University · Leiden University Medical Center · Centre for Human Drug Research

   Affiliation as printed

   Centre for Human Drug Research Leiden The Netherlands

   Leiden University Medical Centre Leiden The Netherlands

   Centre for Human Drug Research, Leiden, The Netherlands

   Leiden University Medical Centre, Leiden, The Netherlands

4. Geert Jan Groeneveld corresponding Aachen Centre for Human Drug Research Leiden the Netherlands Centre for Human Drug Research (CHDR)

   Leiden University · Leiden University Medical Center · Centre for Human Drug Research

   Affiliation as printed

   Centre for Human Drug Research Leiden The Netherlands

   Leiden University Medical Centre Leiden The Netherlands

   Centre for Human Drug Research, Leiden, The Netherlands

   Leiden University Medical Centre, Leiden, The Netherlands