title: Pharmacokinetics of surotomycin from phase 1 single and multiple ascending dose studies in healthy volunteers.
abstract: 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.
  
  
  
  Safety, 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.
  
  
  
  Participants 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.
  
  
  
  Both 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.
  
  
  
  NCT02835118 and NCT02835105 . Retrospectively registered, July 13 2016.
authors.affiliation: Merck & Co., Inc., Kenilworth, NJ, USA.
authors.forename: Gurudatt
authors.initials: G
authors.lastname: Chandorkar
authors.affiliation: Merck & Co., Inc., Kenilworth, NJ, USA.
authors.forename: Qiao
authors.initials: Q
authors.lastname: Zhan
authors.affiliation: Merck & Co., Inc., Kenilworth, NJ, USA.
authors.forename: Julie
authors.initials: J
authors.lastname: Donovan
authors.affiliation: Merck & Co., Inc., Kenilworth, NJ, USA.
authors.forename: Shruta
authors.initials: S
authors.lastname: Rege
authors.affiliation: Merck & Co., Inc., Kenilworth, NJ, USA. hpatino@ITS.JNJ.com.|Janssen Research and Development, Child Health Innovation Leadership Department - CHILD, 920 Route 202 South, Raritan, NJ, 08869, USA. hpatino@ITS.JNJ.com.
authors.forename: Hernando
authors.initials: H
authors.lastname: Patino
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D005500:Follow-Up Studies; D064368:Healthy Volunteers; D006801:Humans; D055666:Lipopeptides / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male; D008875:Middle Aged; D010456:Peptides, Cyclic / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: C574454:CB-183,315; D055666:Lipopeptides; D010456:Peptides, Cyclic
keywords: Clostridium difficile; Clostridium difficile infection; Clostridium difficile-associated diarrhea; Surotomycin