Disposition and Metabolism of Ralfinamide, a Novel Na-Channel Blocker, in Healthy Male Volunteers

Abstract

Ralfinamide is an α-aminoamide derivative with ion channel blocking properties, acting both peripherally and centrally through different molecular targets important in pain control. Absorption, blood and plasma time courses, and urinary and faecal excretion of total radioactivity were assessed in 6 male healthy volunteers administered a single oral dose of 320 mg ¹⁴C-(S)-ralfinamide. Pharmacokinetics of the parent drug were investigated over 120 h, urinary and plasma metabolites up to 192 h post-dose. ¹⁴C-(S)-ralfinamide was rapidly and completely absorbed. Ralfinamide and the dealkylated ralfinamide metabolite (NW-1716) represented the majority of plasma radioactivity. Plasma elimination of the parent compound occurred mono-exponentially (half-life approx. 15 h). ¹⁴C-radioactivity was eliminated in a bi-phasic manner (terminal half-life of 60 and 24 h for plasma and whole blood, respectively). Plasma-concentrations of unchanged ralfinamide were significantly lower than radioactivity concentrations, indicating metabolism of the parent compound. At 192 h post-dose the total balance of radioactivity was almost complete (95%). The main route of excretion was via the kidneys (94% of the dose). Major metabolites identified in urine and plasma were the N-dealkylated acid of ralfinamide and deaminated ralfinamide acid (NW-1799). Other metabolites, in particular the product of glucuronide conjugation N-dealkylated-β-glucuronide, were identified.

Disposition and Metabolism of Safinamide, a Novel Drug for Parkinson's Disease, in Healthy Male Volunteers

“…N-dealkylation was postulated as a major metabolic pathway also for ralfinamide, an α-aminoamide derivative analogue of safinamide [19]. …”

Synthesis and Evaluation of Novel α-Aminoamides Containing an Indole Moiety for the Treatment of Neuropathic Pain

“…Data from animal models of inflammatory and neuropathic pain have suggested that ralfinamide exhibits a significant analgesic effect while also having a well-tolerated safety profile [6,7,8]. Moreover, ralfinamide is the only small molecule drug in a late-stage clinical trial for the treatment of neuropathic pain [9,10,11,12,13]. However, the anti-allodynic efficacy and Nav1.7-selectivity of ralfinamide need further improvement.…”

Synthesis and Evaluation of Novel α-Aminoamides Containing Benzoheterocyclic Moiety for the Treatment of Pain

“…However, achieving selectivity for specific subtypes with small-molecule inhibitors has been challenging [19,20]. α-Aminoamide derivatives such as ralfinamide were previously developed as potential drug candidates for the specific treatment of neuropathic pain [21,22]. Studying the relationship between target selectivity and potency for novel α-aminoamide derivatives is critically needed.…”