Clostridium difficile causes antibiotic associated diarrhea and is a major public health concern. Current therapies disrupt the protective intestinal flora, do not reliably prevent recurrent infections and will be decreasingly effective should less susceptible strains emerge. CRS3123 is an oral agent that inhibits bacterial methionyl-tRNA synthetase, has potent activity against C. difficile and aerobic Gram positive bacteria, but little activity against Gram negative bacteria, including anaerobes. This first-in-human, double-blind, placebo-controlled, dose-escalation study evaluated the safety and systemic exposure of CRS3123 after a single oral dose in healthy adults. Five cohorts of eight subjects, each, received CRS3123 or placebo in a 3:1 ratio. Doses for the active arms were 100mg, 200mg, 400mg, 800mg and 1200 mg respectively. Blood and urine were collected for pharmacokinetic analysis. CRS3123 concentrations were measured with validated LC/MS/MS techniques. There were no serious adverse events or immediate allergic reactions during administration of CRS3123. In the CRS3123-treated groups, the most frequent adverse events were decreased hemoglobin, headache, and abnormal urine analysis; all adverse events in the active treatment groups were mild to moderate, and their frequency did not increase with dose. Although CRS3123 systemic exposure increased at higher doses, the increase was less than dose proportional. Absorbed drug was glucuronidated at reactive amino groups on the molecule which precluded accurate pharmacokinetic analysis of the parent drug. Overall, CRS3123 was well tolerated over this wide range of doses. This safety profile supports further investigation of CRS3123 as a treatment for C. difficile infections.
This trial is registered at ClinicalTrials.gov, number NCT01551004.
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