PMID- 32041717
OWN - NLM
STAT- MEDLINE
DCOM- 20210405
LR  - 20210413
IS  - 1098-6596 (Electronic)
IS  - 0066-4804 (Print)
IS  - 0066-4804 (Linking)
VI  - 64
IP  - 5
DP  - 2020 Apr 21
TI  - Safety and Pharmacokinetic Characterization of Nacubactam, a Novel beta-Lactamase 
      Inhibitor, Alone and in Combination with Meropenem, in Healthy Volunteers.
LID - 10.1128/AAC.02229-19 [doi]
LID - e02229-19
AB  - Nacubactam is a novel beta-lactamase inhibitor with dual mechanisms of action as an 
      inhibitor of serine beta-lactamases (classes A and C and some class D) and an 
      inhibitor of penicillin binding protein 2 in Enterobacteriaceae The safety, 
      tolerability, and pharmacokinetics of intravenous nacubactam were evaluated in 
      single- and multiple-ascending-dose, placebo-controlled studies. Healthy 
      participants received single ascending doses of nacubactam of 50 to 8,000 mg, 
      multiple ascending doses of nacubactam of 1,000 to 4,000 mg every 8 h (q8h) for 
      up to 7 days, or nacubactam of 2,000 mg plus meropenem of 2,000 mg q8h for 6 days 
      after a 3-day lead-in period. Nacubactam was generally well tolerated, with the 
      most frequently reported adverse events (AEs) being mild to moderate 
      complications associated with intravenous access and headache. There was no 
      apparent relationship between drug dose and the pattern, incidence, or severity 
      of AEs. No clinically relevant dose-related trends were observed in laboratory 
      safety test results. No serious AEs, dose-limiting AEs, or deaths were reported. 
      After single or multiple doses, nacubactam pharmacokinetics appeared linear, and 
      exposure increased in an approximately dose-proportional manner across the dose 
      range investigated. Nacubactam was excreted largely unchanged into urine. 
      Coadministration of nacubactam with meropenem did not significantly alter the 
      pharmacokinetics of either drug. These findings support the continued clinical 
      development of nacubactam and demonstrate the suitability of meropenem as a 
      potential beta-lactam partner for nacubactam. (The studies described in this paper 
      have been registered at ClinicalTrials.gov under NCT02134834 [single ascending 
      dose study] and NCT02972255 [multiple ascending dose study].).
CI  - Copyright (c) 2020 Mallalieu et al.
FAU - Mallalieu, Navita L
AU  - Mallalieu NL
AD  - Roche Innovation Center, New York, New York, USA.
FAU - Winter, Erica
AU  - Winter E
AD  - Roche Innovation Center, New York, New York, USA.
FAU - Fettner, Scott
AU  - Fettner S
AD  - Roche Innovation Center, New York, New York, USA.
FAU - Patel, Katie
AU  - Patel K
AD  - Roche Innovation Center, Welwyn, United Kingdom.
FAU - Zwanziger, Elke
AU  - Zwanziger E
AD  - Roche Innovation Center, Basel, Switzerland.
FAU - Attley, Gemma
AU  - Attley G
AD  - Roche Innovation Center, New York, New York, USA.
FAU - Rodriguez, Ignacio
AU  - Rodriguez I
AD  - Roche Innovation Center, New York, New York, USA.
FAU - Kano, Akiko
AU  - Kano A
AD  - Meiji Seika Pharma Co., Ltd., Tokyo, Japan.
FAU - Salama, Sameeh M
AU  - Salama SM
AD  - Fedora Pharmaceuticals, Inc., Edmonton, Alberta, Canada.
FAU - Bentley, Darren
AU  - Bentley D
AD  - Roche Innovation Center, Welwyn, United Kingdom.
FAU - Geretti, Anna Maria
AU  - Geretti AM
AD  - Roche Innovation Center, Basel, Switzerland anna_maria.geretti@roche.com.
AD  - Institute of Infection and Global Health, University of Liverpool, Liverpool, 
      United Kingdom.
LA  - eng
SI  - ClinicalTrials.gov/NCT02134834
SI  - ClinicalTrials.gov/NCT02972255
GR  - HHSO100201600038C/HH/HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
DEP - 20200421
PL  - United States
TA  - Antimicrob Agents Chemother
JT  - Antimicrobial agents and chemotherapy
JID - 0315061
RN  - 0 (Anti-Bacterial Agents)
RN  - 0 (Azabicyclo Compounds)
RN  - 0 (Drug Combinations)
RN  - 0 (Lactams)
RN  - 0 (beta-Lactamase Inhibitors)
RN  - 832O37V7MZ (nacubactam)
RN  - FV9J3JU8B1 (Meropenem)
SB  - IM
MH  - Adolescent
MH  - Adult
MH  - Aged
MH  - Anti-Bacterial Agents/*adverse effects/*pharmacokinetics
MH  - Area Under Curve
MH  - Azabicyclo Compounds/*adverse effects/*pharmacokinetics
MH  - Dose-Response Relationship, Drug
MH  - Double-Blind Method
MH  - Drug Combinations
MH  - Drug Interactions
MH  - Electrocardiography/drug effects
MH  - Female
MH  - Humans
MH  - Lactams/*adverse effects/*pharmacokinetics
MH  - Male
MH  - Meropenem/*adverse effects/*pharmacokinetics
MH  - Middle Aged
MH  - Patient Safety
MH  - Young Adult
MH  - beta-Lactamase Inhibitors/*adverse effects/*pharmacokinetics
PMC - PMC7179653
OTO - NOTNLM
OT  - beta-lactam
OT  - beta-lactamase inhibitor
OT  - meropenem
OT  - multiple ascending dose
OT  - nacubactam
OT  - pharmacokinetics
OT  - phase I
OT  - single ascending dose
EDAT- 2020/02/12 06:00
MHDA- 2021/04/07 06:00
PMCR- 2020/04/21
CRDT- 2020/02/12 06:00
PHST- 2019/11/07 00:00 [received]
PHST- 2020/02/06 00:00 [accepted]
PHST- 2020/02/12 06:00 [pubmed]
PHST- 2021/04/07 06:00 [medline]
PHST- 2020/02/12 06:00 [entrez]
PHST- 2020/04/21 00:00 [pmc-release]
AID - AAC.02229-19 [pii]
AID - 02229-19 [pii]
AID - 10.1128/AAC.02229-19 [doi]
PST - epublish
SO  - Antimicrob Agents Chemother. 2020 Apr 21;64(5):e02229-19. doi: 
      10.1128/AAC.02229-19. Print 2020 Apr 21.