Safety evaluation of glutaric acid as a novel pharmaceutical salt for first-in-human dosing.

Salt selection is critical in pharmaceutical development. Glutaric acid, an endogenous dicarboxylic acid, offers potential advantages as a counterion but is underexplored in pharmaceutical applications. The nonclinical safety of glutaric acid as a pharmaceutical counterion was assessed using LY3972406 hemi-glutarate hemi-hydrate (HG) as a model, with direct comparison to the LY3972406-hydrochloride (HCl) salt. Comprehensive safety assessments included genetic toxicology (Ames, in vitro and in vivo micronucleus tests), hazard evaluation (phototoxicity, and dermal and corneal irritation), and repeat-dose toxicity studies in rats and dogs. Comparative studies evaluated LY3972406-HCl versus LY3972406-HG, and chronic studies assessed glutaric acid alone and as part of the LY3972406-HG salt. Glutaric acid was nongenotoxic. LY3972406-HG showed no phototoxicity and only mild, nonadverse dermal and ocular irritation in hazard assessments. Glutaric acid was well-tolerated by rats and dogs in repeat-dose toxicity studies, with no treatment-related adverse effects. When LY3972406-HG was administered at glutaric acid equivalent doses up to 31 mg/kg/d, all findings were nonadverse, and likely attributable to the active pharmaceutical ingredient LY3972406. Glutaric acid demonstrates a favorable nonclinical safety profile with no genotoxicity and was tolerated at up to 40 mg/kg/d in chronic toxicity studies. Direct comparison with HCl salt confirmed equivalent safety and exposure profiles, supporting glutaric acid as a viable alternative to HCl in pharmaceutical development. Glutaric acid is a promising pharmaceutical counterion that lacks regulatory safety data. This first comprehensive Good Laboratory Practice-compliant nonclinical safety evaluation supports the viability of glutaric acid as an alternative pharmaceutical counterion to hydrochloride salts in drug development.