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- Title
A randomized, double-blind, placebo-controlled, single and multiple ascending dose Phase 1 study to determine the safety, pharmacokinetics and food and faecal microbiome effects of ibezapolstat administered orally to healthy subjects.
- Authors
Garey, Kevin W; Begum, Khurshida; Lancaster, Chris; Gonzales-Luna, Anne; Bui, Dinh; Mercier, Julie; Yue, Corinne Seng; Ducharme, Murray P; Hu, Ming; Vince, Bradley; Silverman, Michael H; Alam, M Jahangir; Kankam, Martin; Seng Yue, Corinne
- Abstract
<bold>Background: </bold>Clostridioides difficile infection is the most common cause of healthcare-associated infections in the USA, with limited treatment options. Ibezapolstat is a novel DNA polymerase IIIC inhibitor with in vitro activity against C. difficile.<bold>Objectives and Methods: </bold>Randomized, double-blind, placebo-controlled study to assess the safety, tolerability and pharmacokinetics of ibezapolstat in healthy volunteers. Microbiome changes associated with ibezapolstat were compared with vancomycin over a 10 day course using shotgun metagenomics.<bold>Results: </bold>A total of 62 subjects aged 31 ± 7 years (45% female; average BMI: 25 ± 3 kg/m2) were randomized. Ibezapolstat was well tolerated with a safety signal similar to placebo. Ibezapolstat had minimal systemic absorption with the majority of plasma concentrations less than 1 µg/mL. In the multiday, ascending dose study, ibezapolstat concentrations of 2000 µg/g of stool were observed by Day 2 and for the remainder of the dosing time period. In the multiday, multiple-dose arm, baseline microbiota was comparable between subjects that received ibezapolstat compared with vancomycin. At Day 10 of dosing, differential abundance analysis and β-diversity demonstrated a distinct difference between the microbiome in subjects given vancomycin compared with either dose of ibezapolstat (P = 0.006). α-Diversity changes were characterized as an increase in the Actinobacteria phylum in subjects that received ibezapolstat and an increase in Proteobacteria in subjects given vancomycin.<bold>Conclusions: </bold>Ibezapolstat was shown to be safe and well tolerated, with minimal systemic exposure, high stool concentrations and a distinct microbiome profile compared with oral vancomycin. These results support further clinical development of ibezapolstat for patients with C. difficile infection.
- Subjects
DNA polymerases; PHARMACOKINETICS; PLACEBOS; VANCOMYCIN; TIME measurements; FECES
- Publication
Journal of Antimicrobial Chemotherapy (JAC), 2020, Vol 75, Issue 12, p3635
- ISSN
0305-7453
- Publication type
journal article
- DOI
10.1093/jac/dkaa364