PMID- 27527080
OWN - NLM
STAT- MEDLINE
DCOM- 20170718
LR  - 20181113
IS  - 1098-6596 (Electronic)
IS  - 0066-4804 (Print)
IS  - 0066-4804 (Linking)
VI  - 60
IP  - 10
DP  - 2016 Oct
TI  - Phase 1 Study of the Safety, Tolerability, and Pharmacokinetics of the 
      beta-Lactamase Inhibitor Vaborbactam (RPX7009) in Healthy Adult Subjects.
PG  - 6326-32
LID - 10.1128/AAC.00568-16 [doi]
AB  - Vaborbactam (formerly RPX7009) is a member of a new class of beta-lactamase 
      inhibitor with pharmacokinetic properties similar to those of many beta-lactams, 
      including carbapenems. The pharmacokinetics and safety of vaborbactam were 
      evaluated in 80 healthy adult subjects in a first-in-human randomized, 
      placebo-controlled, double-blind, sequential single- and multiple-ascending-dose 
      study. A total of 10 dose cohorts were enrolled in the study, with 6 subjects 
      randomized to receive 250 to 2,000 mg of vaborbactam and 2 subjects randomized to 
      receive placebo in each cohort. Maximum concentrations for vaborbactam were 
      achieved at the end of the 3-h infusion. Vaborbactam exposure (Cmax and area 
      under the concentration-time curve [AUC]) increased in a dose-proportional manner 
      following multiple doses. There was no evidence of accumulation with multiple 
      doses, consistent with the terminal half-life of  approximately 2 h. Both the volume of 
      distribution (Vss) and plasma clearance were independent of dose. For the 
      2,000-mg dose, the plasma clearance was 0.17 +/- 0.03 liters/h, the AUC from 0 h to 
      infinity (AUC0-infinity) was 144.00 +/- 13.90 mg . h/liter, and the Vss was 21.80 +/- 2.26 
      mg . h/liter. Urinary recovery was 80% or greater over 48 h across all dose 
      groups. No subjects discontinued the study due to adverse events (AEs), and no 
      serious AEs (SAEs) were observed. All AEs were mild to moderate and similar among 
      the vaborbactam- and placebo-treated subjects, with mild lethargy as the only 
      unique AE reported with the high dose of vaborbactam. Overall, this study 
      revealed the safety, tolerability, and pharmacokinetic profile of vaborbactam and 
      formed the basis for advancement into patient studies in combination with 
      meropenem, including treatment of patients with carbapenem-resistant 
      Enterobacteriaceae (CRE) infections. (This study is registered at 
      ClinicalTrials.gov under identifier NCT01751269.).
CI  - Copyright (c) 2016, American Society for Microbiology. All Rights Reserved.
FAU - Griffith, David C
AU  - Griffith DC
AD  - The Medicines Company, San Diego, California, USA david.griffith@themedco.com.
FAU - Loutit, Jeffery S
AU  - Loutit JS
AD  - The Medicines Company, San Diego, California, USA.
FAU - Morgan, Elizabeth E
AU  - Morgan EE
AD  - The Medicines Company, San Diego, California, USA.
FAU - Durso, Stephanie
AU  - Durso S
AD  - The Medicines Company, San Diego, California, USA.
FAU - Dudley, Michael N
AU  - Dudley MN
AD  - The Medicines Company, San Diego, California, USA.
LA  - eng
SI  - ClinicalTrials.gov/NCT01751269
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Randomized Controlled Trial
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20160923
PL  - United States
TA  - Antimicrob Agents Chemother
JT  - Antimicrobial agents and chemotherapy
JID - 0315061
RN  - 0 (Boronic Acids)
RN  - 0 (Heterocyclic Compounds, 1-Ring)
RN  - 0 (RPX7009)
SB  - IM
MH  - Administration, Intravenous
MH  - Adult
MH  - Boronic Acids/*administration & dosage/adverse effects/*pharmacokinetics
MH  - Female
MH  - Half-Life
MH  - Healthy Volunteers
MH  - Heterocyclic Compounds, 1-Ring/*administration & dosage/adverse 
      effects/*pharmacokinetics
MH  - Humans
MH  - Male
PMC - PMC5038296
EDAT- 2016/08/17 06:00
MHDA- 2017/07/19 06:00
PMCR- 2017/04/01
CRDT- 2016/08/17 06:00
PHST- 2016/03/11 00:00 [received]
PHST- 2016/07/26 00:00 [accepted]
PHST- 2016/08/17 06:00 [entrez]
PHST- 2016/08/17 06:00 [pubmed]
PHST- 2017/07/19 06:00 [medline]
PHST- 2017/04/01 00:00 [pmc-release]
AID - AAC.00568-16 [pii]
AID - 00568-16 [pii]
AID - 10.1128/AAC.00568-16 [doi]
PST - epublish
SO  - Antimicrob Agents Chemother. 2016 Sep 23;60(10):6326-32. doi: 
      10.1128/AAC.00568-16. Print 2016 Oct.