PMID- 27872075
OWN - NLM
STAT- MEDLINE
DCOM- 20170918
LR  - 20181231
IS  - 1098-6596 (Electronic)
IS  - 0066-4804 (Print)
IS  - 0066-4804 (Linking)
VI  - 61
IP  - 2
DP  - 2017 Feb
TI  - Pharmacokinetic-Pharmacodynamic Evaluation of Gepotidacin against Gram-Positive 
      Organisms Using Data from Murine Infection Models.
LID - 10.1128/AAC.00115-16 [doi]
LID - e00115-16
AB  - Gepotidacin (formerly called GSK2140944) is a novel triazaacenaphthylene 
      bacterial topoisomerase inhibitor with in vitro activity against conventional and 
      biothreat pathogens, including Staphylococcus aureus and Streptococcus pneumoniae 
      Using neutropenic murine thigh and lung infection models, the 
      pharmacokinetics-pharmacodynamics (PK-PD) of gepotidacin against S. aureus and S. 
      pneumoniae were characterized. Candidate models were fit to single-dose PK data 
      from uninfected mice (for doses of 16 to 128 mg/kg of body weight given 
      subcutaneously [s.c.]). Dose fractionation studies (1 isolate/organism; 2 to 512 
      mg/kg/day) and dose-ranging studies (5 isolates/organism; 2 to 2,048 mg/kg/day; 
      MIC ranges of 0.5 to 2 mg/liter for S. aureus and 0.125 to 1 mg/liter for S. 
      pneumoniae) were conducted. The presence of an in vivo postantibiotic effect 
      (PAE) was also evaluated. Relationships between the change from baseline in 
      log(10) CFU at 24 h and the ratio of the free-drug plasma area under the 
      concentration-time curve (AUC) to the MIC (AUC/MIC ratio), the ratio of the 
      maximum concentration of drug in plasma (C(max)) to the MIC (C(max)/MIC ratio), 
      and the percentage of a 24-h period that the drug concentration exceeded the MIC 
      (%T>MIC) were evaluated using Hill-type models. Plasma and epithelial lining 
      fluid (ELF) PK data were best fit by a four-compartment model with linear 
      distributional clearances, a capacity-limited clearance, and a first-order 
      absorption rate. The ELF penetration ratio in uninfected mice was 0.65. Since the 
      growth of both organisms was poor in the murine lung infection model, lung 
      efficacy data were not reported. As determined using the murine thigh infection 
      model, the free-drug plasma AUC/MIC ratio was the PK-PD index most closely 
      associated with efficacy (r(2) = 0.936 and 0.897 for S. aureus and S. pneumoniae, 
      respectively). Median free-drug plasma AUC/MIC ratios of 13.4 and 58.9 for S. 
      aureus, and 7.86 and 16.9 for S. pneumoniae, were associated with net bacterial 
      stasis and a 1-log(10) CFU reduction from baseline, respectively. 
      Dose-independent PAE durations of 3.07 to 12.5 h and 5.25 to 8.46 h were 
      demonstrated for S. aureus and S. pneumoniae, respectively.
CI  - Copyright (c) 2017 American Society for Microbiology.
FAU - Bulik, Catharine C
AU  - Bulik CC
AD  - Institute for Clinical Pharmacodynamics, Schenectady, New York, USA.
FAU - Okusanya, Olanrewaju O
AU  - Okusanya OO
AD  - Institute for Clinical Pharmacodynamics, Schenectady, New York, USA.
FAU - Lakota, Elizabeth A
AU  - Lakota EA
AD  - Institute for Clinical Pharmacodynamics, Schenectady, New York, USA.
FAU - Forrest, Alan
AU  - Forrest A
AD  - Institute for Clinical Pharmacodynamics, Schenectady, New York, USA.
FAU - Bhavnani, Sujata M
AU  - Bhavnani SM
AD  - Institute for Clinical Pharmacodynamics, Schenectady, New York, USA.
FAU - Hoover, Jennifer L
AU  - Hoover JL
AD  - GlaxoSmithKline, Collegeville, Pennsylvania, USA.
FAU - Andes, David R
AU  - Andes DR
AD  - University of Wisconsin, Madison, Wisconsin, USA.
FAU - Ambrose, Paul G
AU  - Ambrose PG
AD  - Institute for Clinical Pharmacodynamics, Schenectady, New York, USA 
      PAmbrose@ICPD.com.
LA  - eng
PT  - Journal Article
DEP - 20170124
PL  - United States
TA  - Antimicrob Agents Chemother
JT  - Antimicrobial agents and chemotherapy
JID - 0315061
RN  - 0 (Acenaphthenes)
RN  - 0 (Anti-Bacterial Agents)
RN  - 0 (Heterocyclic Compounds, 3-Ring)
RN  - DVF0PR037D (gepotidacin)
SB  - IM
MH  - Acenaphthenes/administration & dosage/*pharmacokinetics
MH  - Animals
MH  - Anti-Bacterial Agents/administration & dosage/*pharmacokinetics
MH  - Area Under Curve
MH  - Disease Models, Animal
MH  - Dose-Response Relationship, Drug
MH  - Female
MH  - Heterocyclic Compounds, 3-Ring/administration & dosage/*pharmacokinetics
MH  - Mice, Inbred Strains
MH  - Microbial Sensitivity Tests
MH  - Pneumococcal Infections/*drug therapy
MH  - Pneumonia, Staphylococcal/drug therapy
MH  - Staphylococcal Infections/*drug therapy
MH  - Staphylococcus aureus/drug effects
MH  - Streptococcus pneumoniae/drug effects
MH  - Thigh/microbiology
PMC - PMC5278741
OTO - NOTNLM
OT  - Staphylococcus aureus
OT  - Streptococcus pneumoniae
OT  - gepotidacin
EDAT- 2016/11/23 06:00
MHDA- 2017/09/19 06:00
PMCR- 2017/07/24
CRDT- 2016/11/23 06:00
PHST- 2016/01/14 00:00 [received]
PHST- 2016/11/07 00:00 [accepted]
PHST- 2016/11/23 06:00 [pubmed]
PHST- 2017/09/19 06:00 [medline]
PHST- 2016/11/23 06:00 [entrez]
PHST- 2017/07/24 00:00 [pmc-release]
AID - AAC.00115-16 [pii]
AID - 00115-16 [pii]
AID - 10.1128/AAC.00115-16 [doi]
PST - epublish
SO  - Antimicrob Agents Chemother. 2017 Jan 24;61(2):e00115-16. doi: 
      10.1128/AAC.00115-16. Print 2017 Feb.