Abstract
BackgroundSurotomycin, a novel, orally administered, cyclic, lipopeptide antibacterial in development for the treatment of Clostridium difficile-associated diarrhea, has demonstrated minimal intestinal absorption in animal models.MethodsSafety, tolerability, and plasma pharmacokinetics of single and multiple ascending oral doses (SAD/MAD) of surotomycin in healthy volunteers were characterized in two randomized, double-blind, placebo-controlled, phase 1 studies.ResultsParticipants were sequentially enrolled into one of four SAD (500, 1000, 2000, 4000 mg surotomycin) or three MAD (250, 500, 1000 mg surotomycin twice/day for 14 days) cohorts. Ten subjects were randomized 4:1 into each cohort to receive surotomycin or placebo. Surotomycin plasma concentrations rose as dose increased (maximum plasma concentration [Cmax]: 10.5, 21.5, 66.6, and 86.7 ng/mL). Systemic levels were generally low, with peak median surotomycin plasma concentrations observed 6–12 h after the first dose. In the MAD study, surotomycin plasma concentrations were higher on day 14 (Cmax: 25.5, 37.6, and 93.5 ng/mL) than on day 1 (Cmax: 6.8, 11.0, and 21.1 ng/mL for increasing doses), indicating accumulation. In the SAD study, <0.01% of the administered dose was recovered in urine. Mean surotomycin stool concentration from the 1000 mg MAD cohort was 6394 μg/g on day 5. Both cohorts were well tolerated with all adverse events reported as mild to moderate.ConclusionBoth SAD and MAD studies of surotomycin demonstrated minimal systemic exposure, with feces the primary route of elimination following oral administration; consistent with observations with similar compounds, such as fidaxomicin. Results of these phase 1 studies support the continued clinical development of surotomycin for the treatment of Clostridium difficile-associated diarrhea.Trial registrationNCT02835118 and NCT02835105. Retrospectively registered, July 13 2016.
Highlights
Surotomycin, a novel, orally administered, cyclic, lipopeptide antibacterial in development for the treatment of Clostridium difficile-associated diarrhea, has demonstrated minimal intestinal absorption in animal models
Subject demographics and characteristics Both study groups were enrolled to completion with four 10-subject cohorts randomized in the single oral doses (SAD) study and three cohorts of the same size randomized in the multiple ascending dose (MAD) study
Participants in the MAD study receiving placebo had a mean age of 48.8 years and a body mass index (BMI) of 25.8 kg/m2
Summary
Surotomycin, a novel, orally administered, cyclic, lipopeptide antibacterial in development for the treatment of Clostridium difficile-associated diarrhea, has demonstrated minimal intestinal absorption in animal models. Clostridium difficile-associated diarrhea (CDAD) is a key cause of hospital- and community-acquired diarrhea and is associated with longer length of hospital stay, increased medical costs, and high rates of morbidity and mortality [1,2,3]. Despite having a clinical response rate of ~73 to 85%, vancomycin and metronidazole treatments are associated with recurrent CDAD in up to 45% of patients [8,9,10,11]. An ideal agent for the treatment of CDAD should be associated with low levels of systemic absorption, resulting in high concentrations of the drug in the colon, combined with a narrow spectrum of activity against C
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
