PMID- 29311072
OWN - NLM
STAT- MEDLINE
DCOM- 20190514
LR  - 20231213
IS  - 1098-6596 (Electronic)
IS  - 0066-4804 (Print)
IS  - 0066-4804 (Linking)
VI  - 62
IP  - 3
DP  - 2018 Mar
TI  - Pharmacokinetics, Safety, and Tolerability of Cefiderocol, a Novel Siderophore 
      Cephalosporin for Gram-Negative Bacteria, in Healthy Subjects.
LID - 10.1128/AAC.02163-17 [doi]
LID - e02163-17
AB  - Cefiderocol is a novel parenteral siderophore cephalosporin that shows potent 
      efficacy against various Gram-negative bacteria, including carbapenem-resistant 
      strains, in vitro and in preclinical models of infection. The aim of the present 
      study was to evaluate the pharmacokinetics (PK), safety, and tolerability of 
      cefiderocol after both single and multiple dosing by intravenous infusion over 60 
      min in healthy adult subjects. A single-ascending-dose study at doses of 100, 
      250, 500, 1,000, and 2,000 mg was conducted in 40 healthy Japanese males and 
      females (6 individuals receiving the active drug and 2 individuals receiving a 
      placebo per cohort). A multiple-ascending-dose study at doses of 1,000 (two 
      groups) and 2,000 mg every 8 h (q8h) was conducted in 30 healthy Japanese and 
      Caucasian males (8 individuals receiving the active drug and 2 individuals 
      receiving a placebo per cohort). There were no serious or clinically significant 
      adverse events (AEs) observed in either study. A single subject receiving 1,000 
      mg cefiderocol q8h was withdrawn due to AEs. Dose-proportional increases in the 
      maximum plasma concentration (C(max)), the area under the concentration-time 
      curve (AUC) from time zero to the time of the last quantifiable concentration 
      after dosing, and the area under the concentration-time curve extrapolated from 
      time zero to infinity were observed across the dose range of 100 to 2,000 mg. The 
      mean plasma half-life of cefiderocol was 1.98 to 2.74 h. Cefiderocol was 
      primarily excreted unchanged in the urine (61.5% to 68.4% of the dose). There was 
      little accumulation of C(max) and AUC by dosing q8h, and the PK of cefiderocol 
      did not change with multiple dosing. This study indicates that single and 
      multiple intravenous doses of cefiderocol at up to 2,000 mg are well tolerated in 
      healthy subjects and exhibit linear PK at doses up to 2,000 mg.
CI  - Copyright (c) 2018 Saisho et al.
FAU - Saisho, Yutaka
AU  - Saisho Y
AD  - Medical Affairs Department, Shionogi & Co., Ltd., Osaka, Japan 
      yutaka.saisho@shionogi.co.jp.
FAU - Katsube, Takayuki
AU  - Katsube T
AD  - Clinical Research Department, Shionogi & Co., Ltd., Osaka, Japan.
FAU - White, Scott
AU  - White S
AD  - Glaxo SmithKline, Philadelphia, Pennsylvania, USA.
FAU - Fukase, Hiroyuki
AU  - Fukase H
AD  - CPC Clinical Trial Hospital, Kagoshima, Japan.
FAU - Shimada, Jingoro
AU  - Shimada J
AD  - Shionogi & Co., Ltd., Tokyo, Japan.
LA  - eng
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Randomized Controlled Trial
PT  - Research Support, Non-U.S. Gov't
DEP - 20180223
PL  - United States
TA  - Antimicrob Agents Chemother
JT  - Antimicrobial agents and chemotherapy
JID - 0315061
RN  - 0 (Anti-Bacterial Agents)
RN  - 0 (Cephalosporins)
RN  - 0 (Siderophores)
SB  - IM
MH  - Adult
MH  - Anti-Bacterial Agents/blood/*pharmacokinetics/urine
MH  - Area Under Curve
MH  - Cephalosporins/blood/*pharmacokinetics/urine
MH  - Drug Administration Schedule
MH  - Drug Dosage Calculations
MH  - Female
MH  - Half-Life
MH  - Healthy Volunteers
MH  - Humans
MH  - Japan
MH  - Male
MH  - Middle Aged
MH  - Siderophores/blood/*pharmacokinetics/urine
MH  - Cefiderocol
PMC - PMC5826143
OTO - NOTNLM
OT  - Gram-negative bacteria
OT  - cefiderocol
OT  - cephalosporin
OT  - pharmacokinetics
OT  - siderophores
EDAT- 2018/01/10 06:00
MHDA- 2019/05/15 06:00
PMCR- 2018/08/23
CRDT- 2018/01/10 06:00
PHST- 2017/10/23 00:00 [received]
PHST- 2017/12/14 00:00 [accepted]
PHST- 2018/01/10 06:00 [pubmed]
PHST- 2019/05/15 06:00 [medline]
PHST- 2018/01/10 06:00 [entrez]
PHST- 2018/08/23 00:00 [pmc-release]
AID - AAC.02163-17 [pii]
AID - 02163-17 [pii]
AID - 10.1128/AAC.02163-17 [doi]
PST - epublish
SO  - Antimicrob Agents Chemother. 2018 Feb 23;62(3):e02163-17. doi: 
      10.1128/AAC.02163-17. Print 2018 Mar.