PMID- 29133566
OWN - NLM
STAT- MEDLINE
DCOM- 20190422
LR  - 20240314
IS  - 1098-6596 (Electronic)
IS  - 0066-4804 (Print)
IS  - 0066-4804 (Linking)
VI  - 62
IP  - 2
DP  - 2018 Feb
TI  - Pharmacokinetic and Pharmacodynamic Analyses To Determine the Optimal Fixed 
      Dosing Regimen of Iclaprim for Treatment of Patients with Serious Infections 
      Caused by Gram-Positive Pathogens.
LID - 10.1128/AAC.01184-17 [doi]
LID - e01184-17
AB  - Iclaprim is a bacterial dihydrofolate reductase inhibitor that is currently being 
      evaluated in two phase 3 trials for the treatment of patients with acute 
      bacterial skin and skin structure infections (ABSSSI). Prior animal infection 
      model studies suggest that the pharmacokinetic/pharmacodynamic (PK/PD) drivers 
      for efficacy are area under the concentration-time curve from 0 to 24 h at steady 
      state (AUC(0-24ss)), AUC/MIC, and time above the MIC during the dosing interval 
      (T > MIC), while QTc prolongation was associated with the maximal concentration 
      at steady state (C(maxss)) in a thorough QTc phase 1 study. Using PK data 
      collected from 470 patients from the previously conducted phase 3 complicated 
      skin and skin structure infection (cSSSI) trials, population PK modeling and 
      Monte Carlo simulation (MCS) were used to identify a fixed iclaprim dosage 
      regimen for the ongoing phase 3 ABSSSI studies that maximizes AUC(0-24ss), 
      AUC/MIC, and T > MIC while minimizing the probability of a C(maxss) of >/=800 ng/ml 
      relative to the values for the previously employed cSSSI regimen of 0.8 mg/kg of 
      body weight infused intravenously over 0.5 h every 12 h. The MCS analyses 
      indicated that administration of 80 mg as a 2-h infusion every 12 h provides 28%, 
      28%, and 32% increases in AUC(0-24ss), AUC/MIC, and T > MIC, respectively, 
      compared to values for the 0.8-mg/kg cSSSI regimen, while decreasing the 
      probability of a C(maxss) of >/=800 ng/ml, by 9%. Based on PK/PD analyses, 80 mg 
      iclaprim administered over 2 h every 12 h was selected as the dosing scheme for 
      subsequent phase 3 clinical trials.
CI  - Copyright (c) 2018 American Society for Microbiology.
FAU - Lodise, Thomas P
AU  - Lodise TP
AD  - Albany College of Pharmacy and Health Sciences, Albany, New York, USA 
      thomas.lodise@acphs.edu.
FAU - Bosso, John
AU  - Bosso J
AD  - Medical University of South Carolina College of Pharmacy, Charleston, South 
      Carolina, USA.
FAU - Kelly, Colleen
AU  - Kelly C
AD  - Motif BioSciences, Inc., New York, New York, USA.
FAU - Williams, Paul J
AU  - Williams PJ
AD  - Trials by Design, LLC, Stockton, California, USA.
FAU - Lane, James R
AU  - Lane JR
AD  - Trials by Design, LLC, Stockton, California, USA.
FAU - Huang, David B
AU  - Huang DB
AD  - Motif BioSciences, Inc., New York, New York, USA.
LA  - eng
PT  - Clinical Trial, Phase III
PT  - Journal Article
PT  - Randomized Controlled Trial
PT  - Research Support, Non-U.S. Gov't
DEP - 20180125
PL  - United States
TA  - Antimicrob Agents Chemother
JT  - Antimicrobial agents and chemotherapy
JID - 0315061
RN  - 0 (Anti-Bacterial Agents)
RN  - 0 (Pyrimidines)
RN  - 42445HUU0O (iclaprim)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Anti-Bacterial Agents/blood/*pharmacokinetics/pharmacology
MH  - Area Under Curve
MH  - Double-Blind Method
MH  - Drug Administration Schedule
MH  - Drug Dosage Calculations
MH  - Female
MH  - Gram-Positive Bacterial Infections/blood/*drug therapy/microbiology/pathology
MH  - Humans
MH  - Male
MH  - Methicillin-Resistant Staphylococcus aureus/drug effects/growth & development
MH  - Microbial Sensitivity Tests
MH  - Middle Aged
MH  - *Models, Statistical
MH  - Monte Carlo Method
MH  - Pneumococcal Infections/blood/*drug therapy/microbiology/pathology
MH  - Pyrimidines/blood/*pharmacokinetics/pharmacology
MH  - Staphylococcal Skin Infections/blood/*drug therapy/microbiology/pathology
MH  - Streptococcus pneumoniae/drug effects/growth & development
MH  - Vancomycin-Resistant Enterococci/drug effects/growth & development
PMC - PMC5786772
OTO - NOTNLM
OT  - Monte Carlo simulation
OT  - PD
OT  - PK
OT  - iclaprim
EDAT- 2017/11/15 06:00
MHDA- 2019/04/23 06:00
PMCR- 2018/07/25
CRDT- 2017/11/15 06:00
PHST- 2017/06/08 00:00 [received]
PHST- 2017/10/27 00:00 [accepted]
PHST- 2017/11/15 06:00 [pubmed]
PHST- 2019/04/23 06:00 [medline]
PHST- 2017/11/15 06:00 [entrez]
PHST- 2018/07/25 00:00 [pmc-release]
AID - AAC.01184-17 [pii]
AID - 01184-17 [pii]
AID - 10.1128/AAC.01184-17 [doi]
PST - epublish
SO  - Antimicrob Agents Chemother. 2018 Jan 25;62(2):e01184-17. doi: 
      10.1128/AAC.01184-17. Print 2018 Feb.