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    Multiple-Ascending-Dose Phase 1 Clinical Study of the Safety, Tolerability, and Pharmacokinetics of CRS3123, a Narrow-Spectrum Agent with Minimal Disruption of Normal Gut Microbiota

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    Author
    Lomeli, B.K.
    Galbraith, H.
    Ravel, J.
    Date
    2019
    Journal
    Antimicrobial agents and chemotherapy
    Publisher
    American Society for Microbiology
    Type
    Article
    
    Metadata
    Show full item record
    See at
    https://doi.org/10.1128/AAC.01395-19
    Abstract
    CRS3123 is a novel small molecule that potently inhibits methionyl-tRNA synthetase of Clostridioides difficile, inhibiting C. difficile toxin production and spore formation. CRS3123 has been evaluated in a multiple-ascending-dose placebo-controlled phase 1 trial. Thirty healthy subjects, ages 18 to 45 years, were randomized into three cohorts of 10 subjects each, receiving either 200, 400, or 600 mg of CRS3123 (8 subjects per cohort) or placebo (2 subjects per cohort) by oral administration twice daily for 10 days. CRS3123 was generally safe and well tolerated, with no serious adverse events (SAEs) or severe treatment-emergent adverse events (TEAEs) reported. All subjects completed their assigned treatment and follow-up visits, and there were no trends in systemic, vital sign, or laboratory TEAEs. There were no QTcF interval changes or any clinically significant changes in other electrocardiogram (ECG) intervals or morphology. CRS3123 showed limited but detectable systemic uptake; although absorption increased with increasing dose, the increase was less than dose proportional. Importantly, the bulk of the oral dose was not absorbed, and fecal concentrations were substantially above the MIC90 value of 1 μg/ml at all dosages tested. Subjects receiving either of the two lower doses of CRS3123 exhibited minimal disruption of normal gut microbiota after 10 days of twice-daily dosing. CRS3123 was inactive against important commensal anaerobes, including Bacteroides, bifidobacteria, and commensal clostridia. Microbiome data showed favorable differentiation compared to other CDI therapeutics. These results support further development of CRS3123 as an oral agent for the treatment of CDI. (This study has been registered at Clinicaltrials.gov under identifier NCT02106338.). Copyright 2019 Lomeli et al.
    Keyword
    antibiotic
    Clostridioides difficile
    CRS3123
    gut microbiota
    MAD study
    microbiome
    narrow spectrum
    phase 1
    sporulation
    toxin production
    Identifier to cite or link to this item
    https://www.scopus.com/inward/record.uri?eid=2-s2.0-85077017112&doi=10.1128%2fAAC.01395-19&partnerID=40&md5=13d520a795bae29897c7577480b3bfe3; http://hdl.handle.net/10713/11565
    ae974a485f413a2113503eed53cd6c53
    10.1128/AAC.01395-19
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