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.
R. Vickers, Summit Therapeutics: Employee , Salary and Stock options .
N. Robinson, Summit Therapeutics: Consultant , Consulting fee .