TY - JOUR
T1 - Safety, tolerability, systemic exposure, and metabolism of CRS3123, a methionyl-tRNA synthetase inhibitor developed for treatment of Clostridium difficile, in a Phase 1 Study
AU - Nayak, Seema U.
AU - Griffiss, J. Mc Leod
AU - Blumer, Jeffrey
AU - O’Riordan, Mary Ann
AU - Gray, Wesley
AU - McKenzie, Robin
AU - Jurao, Robert A.
AU - An, Amanda T.
AU - Le, Melissa
AU - Bell, Stacie J.
AU - Ochsner, Urs A.
AU - Jarvis, Thale C.
AU - Janjic, Nebojsa
AU - Zenilman, Jonathan M.
N1 - Publisher Copyright:
© 2017 American Society for Microbiology. All Rights Reserved.
PY - 2017/8
Y1 - 2017/8
N2 - 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 and 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 respective active arms were 100 mg, 200 mg, 400 mg, 800 mg, and 1,200 mg. 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. The 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 study has been registered at ClinicalTrials.gov under identifier NCT01551004.)
AB - 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 and 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 respective active arms were 100 mg, 200 mg, 400 mg, 800 mg, and 1,200 mg. 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. The 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 study has been registered at ClinicalTrials.gov under identifier NCT01551004.)
KW - Antimicrobial agents
KW - CRS3123
KW - Clostridium difficile
KW - Glucuronidation
KW - Gram-positive bacteria
KW - Pharmacokinetics
UR - http://www.scopus.com/inward/record.url?scp=85026417389&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85026417389&partnerID=8YFLogxK
U2 - 10.1128/AAC.02760-16
DO - 10.1128/AAC.02760-16
M3 - Article
C2 - 28584140
AN - SCOPUS:85026417389
SN - 0066-4804
VL - 61
JO - Antimicrobial agents and chemotherapy
JF - Antimicrobial agents and chemotherapy
IS - 8
M1 - e02760-16
ER -