PMID- 16887471
OWN - NLM
STAT- MEDLINE
DCOM- 20061114
LR  - 20220317
IS  - 0732-8893 (Print)
IS  - 0732-8893 (Linking)
VI  - 55
IP  - 4
DP  - 2006 Aug
TI  - Population pharmacokinetic modeling and Monte Carlo simulation of varying doses 
      of intravenous metronidazole.
PG  - 303-9
AB  - Population pharmacokinetic modeling and Monte Carlo simulation (MCS) are 
      approaches used to determine probability of target attainment (PTA) of 
      antimicrobial therapy. The objectives of this study were 1) to determine a 
      population pharmacokinetic model (PPM) using metronidazole and 
      hydroxy-metronidazole concentrations from healthy subjects and critically ill 
      patients, and 2) to determine the probability of attaining the pharmacodynamic 
      target area under the plasma concentration (AUC)/MIC ratio >or=70 against 218 
      clinical isolates of Bacteroides fragilis using MCS. Eighteen healthy subjects 
      were randomized to 3 dosages of intravenous metronidazole (500 mg every 8 h, 1000 
      mg day(-1), 1500 mg day(-1)) in an open-label 3-way crossover fashion. Serial 
      blood samples were collected over 25.5 h on the 3rd day of each study period. An 
      additional of 8 critically ill patients received intravenous metronidazole 500 mg 
      every 8 h. Serial blood samples were collected over 8 h after the 2nd day of 
      dosing. Plasma metronidazole and hydroxy-metronidazole concentrations were 
      analyzed using a high-performance liquid chromatographic assay. The 834 plasma 
      concentrations from 62 data sets were simultaneously modeled with Non-Parametric 
      Adaptive Grid population modeling program. A 4-compartment model with a 
      metabolite and zero-order infusion into the central compartment was used. The 
      mean parameter vector and covariance matrix from PPM were inserted into the 
      simulation module of ADAPT II. A 10,000-subject MCS was performed to determine 
      the probability of PTA for a total drug AUC to MIC ratio >or=70 against 218 
      isolates of B. fragilis (MIC range, 0.125-2.0 mg L(-1)). Mean parameter values 
      were CL(non-OH), 3.08 L h(-1); Vc, 35.4 L; K(OH), 0.04 h(-1); CL(OH), 2.78 L 
      h(-1); and V(OH), 9.66 L. The regression values of the observed versus predicted 
      concentrations (r2) of metronidazole and hydroxy-metronidazole were 0.972 and 
      0.980, respectively. The PTA for metronidazole 1500 mg day(-1) or 500 mg every 8 
      h (taken together) and 1000 mg day(-1) were 99.9% and 99.8%, respectively, over 
      the reported MIC distribution range. For an MIC of 4 mg L(-1), the predicted PTA 
      decreased to 80.0% and 28.5%, respectively. A PPM was determined by comodeling 
      metronidazole and hydroxy-metronidazole concentrations from healthy subjects and 
      critically ill patients. Based on this model, attainment of the target 
      pharmacodynamic parameter (AUC/MIC ratio >or=70) against B. fragilis isolates is 
      >99% when MICs are <2 mg L(-1), irrespective of the dosing interval of 24 h.
FAU - Sprandel, Kelly A
AU  - Sprandel KA
AD  - College of Pharmacy, University of Illinois, Chicago, IL 60612, USA.
FAU - Drusano, George L
AU  - Drusano GL
FAU - Hecht, David W
AU  - Hecht DW
FAU - Rotschafer, John C
AU  - Rotschafer JC
FAU - Danziger, Larry H
AU  - Danziger LH
FAU - Rodvold, Keith A
AU  - Rodvold KA
LA  - eng
GR  - M01-RR-13987/RR/NCRR NIH HHS/United States
PT  - Journal Article
PT  - Randomized Controlled Trial
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Diagn Microbiol Infect Dis
JT  - Diagnostic microbiology and infectious disease
JID - 8305899
RN  - 0 (Anti-Infective Agents)
RN  - 140QMO216E (Metronidazole)
SB  - IM
MH  - Administration, Intravesical
MH  - Adult
MH  - Aged
MH  - Aged, 80 and over
MH  - Anti-Infective Agents/administration & dosage/blood/*pharmacokinetics
MH  - Bacteroides fragilis/*drug effects
MH  - Bayes Theorem
MH  - Cross-Over Studies
MH  - Drug Administration Schedule
MH  - Drug Therapy, Computer-Assisted/methods
MH  - Humans
MH  - Metronidazole/administration & dosage/blood/*pharmacokinetics
MH  - Microbial Sensitivity Tests
MH  - Middle Aged
MH  - Monte Carlo Method
MH  - Tissue Distribution
EDAT- 2006/08/05 09:00
MHDA- 2006/11/15 09:00
CRDT- 2006/08/05 09:00
PHST- 2006/08/05 09:00 [pubmed]
PHST- 2006/11/15 09:00 [medline]
PHST- 2006/08/05 09:00 [entrez]
AID - S0732-8893(06)00234-3 [pii]
AID - 10.1016/j.diagmicrobio.2006.06.013 [doi]
PST - ppublish
SO  - Diagn Microbiol Infect Dis. 2006 Aug;55(4):303-9. doi: 
      10.1016/j.diagmicrobio.2006.06.013.