Pharmacokinetics of surotomycin from phase 1 single and multiple ascending dose studies in healthy volunteers

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

Trial registration: NCT02835118 and NCT02835105 . Retrospectively registered, July 13 2016.

Keywords: Clostridium difficile; Clostridium difficile infection; Clostridium difficile-associated diarrhea; Surotomycin.

Figures

Fig. 1

Single ascending dose (a) and multiple ascending dose (b) study overviews

Fig. 2

Median plasma concentration versus time profiles for surotomycin following administration of (a) a single dose, (b) the first dose on day 1, and (c) the morning dose on day 14

Fig. 3

Dose-normalized (a) Cmax and (b) AUC0–∞ of surotomycin following administration of single oral doses of surotomycin. AUC0–∞, area under the concentration-time curve from 0 to infinity Cmax, maximum plasma concentration