1361. Pharmacokinetics and Safety of Ridinilazole (RDZ), a Potential New Therapy for Clostridium difficile Infection (CDI): from Animal Models to Patients
Session: Poster Abstract Session: Novel Agents
Friday, October 5, 2018
Room: S Poster Hall
Posters
  • 106576 Summit - 2018 ID Week_RDZ PK Safety FINAL_26Sep2018_ED.PDF (7.4 MB)
  • Background: CDI is the leading cause of nosocomial diarrhoea associated with 29,000 deaths p.a. in the USA. 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.

    Methods: RDZ levels were measured in plasma and in the GI tract of infected hamster after a single oral dose at 25mg/kg. Quantitative whole body autoradiography (QWBA) and excretion mass balance studies were performed in rats following a single 50mg/kg oral dose of 14C RDZ. In GLP toxicology studies, RDZ was administered orally for 28 days to dogs and rats at 1000 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 2000mg, 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 faeces, and, assessed safety and tolerability.

    Results: In 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 caecum and colon, the site of infection; >99% of radioactivity was excreted in faeces 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.

    Conclusion: In both clinical and non-clinical 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.

    Esther Duperchy, PhD1, Sumita Chowdhury, MD MPH2, Richard Vickers, PhD1 and Neil Robinson, PhD3, (1)R&D, Summit Therapeutics, Abingdon, United Kingdom, (2)R&D, Summit Therapeutics, Cambridge, MA, (3)S.H.B. Enterprises Ltd, Beaconsfield, United Kingdom

    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 .

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