1361. Pharmacokinetics and Safety of Ridinilazole (RDZ), a Potential New Therapy for Clostridium difficile Infection (CDI): From Animal Models to Patients

Abstract

BackgroundCDI is the leading cause of nosocomial diarrhea associated with 29,000 deaths p.a. in the United States. RDZ is a novel oral drug highly selective for C. difficile limiting collateral damage to the gut microbiota. Here we present a combined analysis of all pharmacokinetic (PK) and tolerability data obtained throughout the development of RDZ from animal models to Phase 2, including new human PK data.MethodsRDZ levels were measured in plasma and in the GI tract of infected hamster after a single oral dose at 25 mg/kg. Quantitative whole-body autoradiography (QWBA) and excretion mass balance studies were performed in rats following a single 50 mg/kg oral dose of 14C RDZ. In GLP toxicology studies, RDZ was administered orally for 28 days to dogs and rats at 1,000 mg/kg/day. Toxicokinetic, clinical pathology, and histopathology analysis were performed. The Phase 1 study enrolled 56 healthy male subjects receiving single ascending doses from 2 to 2,000 mg, or, 200 or 500 mg BID for 10 days. The Phase 2 enrolled 100 patients assigned 1:1 to 10 days oral RDZ 200 mg BID or VAN 125 mg QID treatment. Both clinical trials quantified RDZ in plasma and feces, and assessed safety and tolerability.ResultsIn all animal studies, plasma levels of RDZ were below or at the limit of quantification (LOQ, 1.0 ng/mL). In the GI tract of hamsters, RDZ levels were highest in the colon. QWBA and excretion studies showed RDZ accumulated in the cecum and colon, the site of infection; >99% of radioactivity was excreted in feces and no radioactivity was detected systemically. 28 days repeat dosing in dog and rat resulted in no observations from treatment, histopathology or in-life parameters. In Phase 1 and 2 studies, RDZ plasma levels were generally near or below the LOQ (0.1 ng/mL). Concomitant medications, CDI severity, and age had no impact on exposure. In Phase 1, AEs were mild with no dose-dependent relationship, occurring and at a similar incidence to placebo. No significant findings from clinical laboratory, ECGs or other assessment were observed. RDZ was well tolerated in Phase 2 with the incidence of AEs and SAEs similar in both RDZ and VAN groups.ConclusionIn both clinical and nonclinical studies to date, RDZ has been well tolerated and associated with low systemic absorption. Further assessment of safety, tolerability, and PK in Phase 3 studies is warranted.Disclosures E. Duperchy, Summit Therapeutics: Employee, Salary. S. Chowdhury, Summit Therapeutics Inc.: Employee and Shareholder, Salary and Shareholder. R. Vickers, Summit Therapeutics: Employee, Salary and Stock options. N. Robinson, Summit Therapeutics: Consultant, Consulting fee.